Substituted-4-aryl-1,4-dihydro-1,6-naphthyridinamides and use thereof

ABSTRACT

The present application relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, a process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders.

RELATED APPLICATIONS/PATENTS AND INCORPORATION BY REFERENCE

This application is a National Stage Application filed under 35 U.S.C.§371 based on International Application No. PCT/EP2008/001257, filedFeb. 19, 2008, which claims priority to German Patent Application Number102007009494.0, filed Feb. 27, 2007, the entire contents each of whichare incorporated herein by reference.

The foregoing applications, and all documents cited therein and alldocuments cited or referenced therein, and all documents cited orreferenced herein, including any U.S. or foreign patents or publishedpatent applications, International patent applications, as well as, anynon-patent literature references and any manufacturer's instructions,are hereby expressly incorporated herein by reference.

The present application relates to novel substituted4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, a process for theirpreparation, their use for the treatment and/or prophylaxis of diseases,and their use for the manufacture of medicaments for the treatmentand/or prophylaxis of diseases, especially cardiovascular disorders.

Aldosterone plays a key part in maintaining fluid and electrolytehomeostasis by promoting, in the epithelium of the distal nephron,sodium retention and potassium secretion, thus contributing to keepingthe extracellular volume constant and thus to regulating blood pressure.Besides this, aldosterone displays direct effects on the structure andfunction of the cardiac and vascular system, but the underlyingmechanisms thereof are not yet fully explained [R. E. Booth, J. P.Johnson, J. D. Stockand, Adv. Physiol. Educ. 26 (1), 8-20 (2002)].

Aldosterone is a steroid hormone which is formed in the adrenal cortex.Its production is regulated indirectly very substantially depending onthe renal blood flow. Any decrease in renal blood flow leads to releasein the kidney of the enzyme renin into the circulating blood. This inturn activates the formation of angiotensin II, which on the one handhas a constricting effect on the arterial blood vessels, but on theother hand also stimulates the formation of aldosterone in the adrenalcortex. Thus, the kidney acts as blood pressure sensor, and thusindirect volume sensor, in the circulating blood and counteracts, viathe renin-angiotensin-aldosterone system, critical losses of volume byon the one hand increasing the blood pressure (angiotensin II effect),and on the other hand, by rebalancing the state of filling of thevascular system by increased reabsorption of sodium and water in thekidney (aldosterone effect).

This control system may be pathologically impaired in diverse ways.Thus, a chronic reduction in renal blood flow (e.g. as a result of heartfailure and the congestion of blood in the venous system caused thereby)leads to a chronically excessive release of aldosterone. In turn this isfollowed by an expansion of the blood volume and thereby increases theweakness of the heart through an excessive supply of volume to theheart. Congestion of blood in the lungs with shortness of breath andformation of edema in the extremities, and ascites and pleural effusionsmay be the result; the renal blood flow falls further. In addition, theexcessive aldosterone effect leads to a reduction in the potassiumconcentration in the blood and in the extracellular fluid. In heartmuscles which have been previously damaged otherwise, cardiacarrhythmias with a fatal outcome may be induced if there is a deviationbelow a critical minimum level. This is likely to be one of the maincauses of the sudden cardiac death which frequently occurs in patientswith heart failure.

In addition, aldosterone is also thought to be responsible for a numberof the myocardial remodeling processes typically to be observed in heartfailure. Thus, hyperaldosteronism is a crucial component in thepathogenesis and prognosis of heart failure which may originally beinduced by various types of damage such as, for example, a myocardialinfarction, a myocardial inflammation or high blood pressure. Thisassumption is supported by the fact that there was a marked reduction inoverall mortality in wide-ranging clinical studies on groups of patientswith chronic heart failure and post acute myocardial infarction throughthe use of aldosterone antagonists [B. Pitt, F. Zannad, W. J. Remme etal., N. Engl. J. Med. 341, 709-717 (1999); B. Pitt, W. Remme, F. Zannadet al., N. Engl. J. Med. 348, 1309-1321 (2003)]. It was possible toachieve this inter alia by reducing the incidence of sudden cardiacdeath.

According to recent studies, a not inconsiderable number of patientssuffering from essential hypertension are also found to have a so-callednormokalemic variant of primary hyperaldosteronism [prevalence up to 11%of all hypertensives: L. Seiler and M. Reincke, DerAldosteron-Renin-Quotient bei sekundärer Hypertonie, Herz 28, 686-691(2003)]. The best diagnostic method for normokalemic hyperaldosteronismis the aldosterone/renin quotient of the corresponding plasmaconcentrations, so that relative elevations in aldosterone in relationto the renin plasma concentrations can also be diagnosed and eventuallytreated. For this reason, a hyperaldosteronism diagnosed in connectionwith essential hypertension is a starting point for a causal andprophylactically worthwhile therapy.

Far less common than the types of hyperaldosteronism detailed above arepathological states in which the impairment either is to be found in thehormone-producing cells of the adrenal itself, or the number or massthereof is increased through hyperplasia or proliferation. Adenomas ordiffuse hyperplasias of the adrenal cortex are the commonest cause ofthe primary hyperaldosteronism referred to as Conn's syndrome, theleading symptoms of which are hypertension and hypokalemic alkalosis.The priority here too, besides surgical removal of the diseased tissue,is medical therapy with aldosterone antagonists [H. A. Kühn and J.Schirmeister (Editors), Innere Medizin, 4th edition, Springer Verlag,Berlin, 1982].

Another pathological state associated typically with an elevation of theplasma aldosterone concentration is advanced cirrhosis of the liver. Thecause of the aldosterone elevation in this case is mainly the restrictedaldosterone breakdown resulting from the impairment of liver function.Volume overload, edema and hypokalemia are the typical consequences,which can be successfully alleviated in clinical practice by aldosteroneantagonists.

The effects of aldosterone are mediated by the mineralocorticoidreceptor which has an intracellular location in the target cells. Thealdosterone antagonists available to date have, like aldosterone itself,a basic steroid structure. The utility of such steroidal antagonists islimited by their interactions with the receptors of other steroidhormones, which in some cases lead to considerable side effects such asgynecomastia and impotence and to discontinuation of the therapy [M. A.Zaman, S. Oparil, D. A. Calhoun, Nature Rev. Drug Disc. 1, 621-636(2002)].

The use of potent, non-steroidal antagonists which are more selectivefor the mineralocorticoid receptor provides the possibility of avoidingthis profile of side effects and thus achieving a distinct therapeuticadvantage.

The object of the present invention is to provide novel compounds whichcan be used as selective mineralocorticoid receptor antagonists for thetreatment of disorders, especially cardiovascular disorders.

EP 0 133 530-A, EP 0 173 933-A, EP 0 189 898-A and EP 0 234 516-Adisclose 4-aryl-substituted 1,4-dihydro-1,6-naphthyridines and-naphthyridinones having a calcium-antagonistic effect for the treatmentof vascular disorders. The pharmacological profile of these compounds isreported inter alia in G. Werner et al., Naunyn-Schmiedeberg's Arch.Pharmacol. 344 (3), 337-344 (1991). In addition,1,4-dihydro-1,6-naphthyridine derivatives are claimed in WO 02/10164 aspotassium channel openers for the treatment of various, in particularurological, disorders. 4-Fluorenonyl- and4-chromenonyl-1,4-dihydropyridine derivatives are described asmineralocorticoid receptor antagonists in WO 2005/087740 and WO2007/009670. WO 2006/066011 discloses4-aryl-3-cyano-1,4-dihydropyridine-5-carboxylic esters and carboxamidesas in some cases dual modulators of steroid hormone receptors and of theL-type calcium channel, and WO 2005/097118 claims compounds having a4-aryl-1,4-dihydropyridine core structure as aldosterone receptorantagonists.

The present invention relates to compounds of the general formula (I)

in which

-   D is N or C—R⁴, in which    -   R⁴ is hydrogen, fluorine, trifluoromethyl or (C₁-C₄)-alkyl,-   Ar is a group of the formula

-   -   in which    -   * is the linkage point,    -   R⁵ is hydrogen, fluorine, chlorine, cyano, nitro,        trifluoromethyl or (C₁-C₄)-alkyl,    -   R⁶ is hydrogen or fluorine,    -   R⁷ is halogen, (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy or        trifluoromethoxy,    -   R⁸ is cyano or nitro,    -   R⁹ is hydrogen, halogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,        (C₁-C₄)-alkylthio or di-(C₁-C₄)-alkylamino, it being possible        for the alkyl group in said (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy and        (C₁-C₄)-alkylthio radicals in each case to be substituted up to        three times by fluorine,        -   or        -   phenyl, which may be substituted by halogen, (C₁-C₄)-alkyl            or trifluoromethyl,    -   R¹⁰ is hydrogen, halogen or (C₁-C₄)-alkyl,    -   E is CH, C—R⁷ or N,    -   and    -   n is the number 0, 1 or 2,        -   it being possible in the case where the substituent R⁷            occurs more than once for its meanings to be identical or            different,

-   R¹ is (C₁-C₄)-alkyl which may be substituted up to three times by    fluorine,

-   R² is (C₁-C₆)-alkyl which may be substituted by (C₃-C₇)-cycloalkyl    or up to three times by fluorine, or is a group of the formula    —SO₂—R¹¹ in which    -   R¹¹ is (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₇)-cycloalkyl,        phenyl or 5- or 6-membered heteroaryl having up to two        heteroatoms from the series N, O and/or S, it being possible for        phenyl and heteroaryl in turn each to be substituted once or        twice, identically or differently, by halogen, cyano, nitro,        (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy and/or        trifluoromethoxy,        and

-   R³ is hydrogen, fluorine, trifluoromethyl or (C₁-C₄)-alkyl,    and the salts, solvates and solvates of the salts thereof.

Compounds of the invention are the compounds of the formula (I) and thesalts, solvates and solvates of the salts thereof; the compounds whichare encompassed by formula (I) and are of the formulae mentionedhereinafter, and the salts, solvates and solvates of the salts thereof,and the compounds which are encompassed by formula (I) and are mentionedhereinafter as exemplary embodiments, and the salts, solvates andsolvates of the salts thereof, insofar as the compounds encompassed byformula (I) and mentioned hereinafter are not already salts, solvatesand solvates of the salts.

The compounds of the invention may, depending on their structure, existin stereoisomeric forms (enantiomers, diastereomers). The presentinvention therefore relates to the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated in a known manner from such mixtures of enantiomersand/or diastereomers.

If the compounds of the invention may occur in tautomeric forms, thepresent invention encompasses all tautomeric forms.

Salts which are preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds of the invention. Alsoencompassed are salts which are themselves unsuitable for pharmaceuticaluses but can be used for example for isolating or purifying thecompounds of the invention.

Physiologically acceptable salts of the compounds of the inventioninclude acid addition salts of mineral acids, carboxylic acids andsulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, malic acid, citric acid, fumaric acid, maleic acid andbenzoic acid.

Physiologically acceptable salts of the compounds of the inventioninclude salts of conventional bases such as, by way of example andpreferably, alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts derived from ammonia or organic amines having 1 to 16 Catoms, such as, by way of example and preferably, ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates refers for the purposes of the invention to those forms of thecompounds of the invention which form, in the solid or liquid state, acomplex by coordination with solvent molecules. Hydrates are a specificform of solvates in which the coordination takes place with water.Hydrates are preferred solvates in the context of the present invention.

The present invention additionally encompasses prodrugs of the compoundsof the invention. The term “prodrugs” encompasses compounds whichthemselves may be biologically active or inactive, but are convertedduring their residence time in the body into compounds of the invention(for example by metabolism or hydrolysis).

In the context of the present invention, the substituents have thefollowing meaning, unless specified otherwise:

(C₁-C₆)-Alkyl and (C₁-C₄)-alkyl represent in the context of theinvention a straight-chain or branched alkyl radical having respectively1 to 6 and 1 to 4 carbon atoms. A straight-chain or branched alkylradical having 1 to 4 carbon atoms is preferred. Mention may be made byway of example and preferably of: methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl,iso-pentyl and n-hexyl.

(C₃-C₇)-Cycloalkyl represents in the context of the invention asaturated monocyclic cycloalkyl group having 3 to 7 carbon atoms.Preference is given to a cycloalkyl radical having 3 to 6 carbon atoms.Mention may be made by way of example and preferably of: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

(C₁-C₄)-Alkoxy represents in the context of the invention astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms.Mention may be made by way of example and preferably of: methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

(C₁-C₄)-Alkylthio represents in the context of the invention astraight-chain or branched alkylthio radical having 1 to 4 carbon atoms.Mention may be made by way of example and preferably of: methylthio,ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio.

Di-(C₁-C₄)-alkylamino represents in the context of the invention anamino group having two identical or different straight-chain or branchedalkyl substituents, each of which have 1 to 4 carbon atoms. Mention maybe made by way of example and preferably of: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N,N-diisopropylamino, N-isopropyl-N-n-propylamino,N-n-butyl-N-methylamino and N-tert-butyl-N-methylamino.

5- or 6-membered heteroaryl represents in the context of the inventionan aromatic heterocycle (heteroaromatic) having 5 or 6 ring atoms whichcomprises one or two ring atoms from the series N, O and/or S and islinked via a ring carbon atom. Mention may be made by way of example andpreferably of: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl,pyridazinyl and pyrazinyl.

Halogen includes in the context of the invention fluorine, chlorine,bromine and iodine. Fluorine or chlorine are preferred.

If radicals in the compounds of the invention are substituted, theradicals may be substituted one or more times, unless specifiedotherwise. In the context of the present invention, all radicals whichoccur more than once have a mutually independent meaning. Substitutionby one, two or three identical or different substituents is preferred.Substitution by one substituent is very particularly preferred.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   D is C—R⁴ in which    -   R⁴ is hydrogen, methyl or trifluoromethyl,-   Ar is a group of the formula

-   -   in which    -   * is the linkage point,    -   R⁵ is hydrogen, fluorine, chlorine or cyano,    -   R⁸ is cyano or nitro,    -   and    -   R⁹ is chlorine, bromine, (C₁-C₄)-alkyl, trifluoromethyl,        (C₁-C₄)-alkoxy, trifluoromethoxy, (C₁-C₄)-alkylthio or        trifluoromethylthio,

-   R¹ is methyl or trifluoromethyl,

-   R² is (C₁-C₄)-alkyl, trifluoromethyl or a group of the formula    —SO₂—R¹¹ in which    -   R¹¹ is (C₁-C₄)-alkyl or trifluoromethyl,        and

-   R³ is hydrogen, methyl or trifluoromethyl,    and the salts, solvates and solvates of the salts thereof.

Particular preference is given in the context of the present inventionto compounds of the formula (I) in which

-   D is C—R⁴ in which    -   R⁴ is hydrogen or methyl,-   Ar is a group of the formula

-   -   in which    -   * is the linkage point    -   and    -   R⁹ is ethyl, methoxy or trifluoromethoxy,

-   R¹ is methyl or trifluoromethyl,

-   R² is methyl, ethyl, n-propyl or isopropyl    and

-   R³ is hydrogen or methyl,    and the salts, solvates and solvates of the salts thereof.

Very particular preference is given to compounds of the formula (I)having the following structures:

and the salts, solvates and solvates of the salts thereof.

In particular preference is given here to enantiomeric compounds havingthe following structures:

-   -   and the salts, solvates and solvates of the salts thereof.

The definitions of radicals indicated specifically in the respectivecombinations or preferred combinations of radicals are replaced asdesired irrespective of the particular combinations indicated for theradicals also by definitions of radicals of other combinations.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention further relates to a process for preparing the compoundsof the invention of the formula (I), characterized in that a compound ofthe formula (II)

in which Ar has the meaning indicated above,is reacted in an inert solvent, where appropriate in the presence of anacid, an acid/base combination and/or a dehydrating agent, with acompound of the formula (III)

in which R¹ has the meaning indicated above, andT is allyl or 2-cyanoethyl,to give a compound of the formula (IV)

in which Ar, T and R¹ each have the meanings indicated above,the latter is then condensed in an inert solvent with a compound of theformula (V)

in which D and R³ have the meanings indicated above,to give a compound of the formula (VI)

in which Ar, D, T, R¹ and R³ each have the meanings indicated above,then the compounds of the formula (VI) are alkylated in an inertsolvent, where appropriate in the presence of a base, with a compound ofthe formula (VII) or a trialkyloxonium salt of the formula (VIII)

in which

-   R¹² is (C₁-C₆)-alkyl which may be substituted by (C₃-C₇)-cycloalkyl    or up to three times by fluorine,-   R^(12A) is methyl or ethyl,-   X is a leaving group such as, for example, halogen, mesylate,    tosylate or triflate,    and-   Y⁻ is a non-nucleophilic anion such as, for example,    tetrafluoroborate,    or in the presence of an acid with a trialkyl orthoformate of the    formula (IX)

in which R^(12A) has the meaning indicated above,to give compounds of the formula (X-A)

in which Ar, D, T, R¹, R³ and R¹² each have the meanings indicatedabove,or the compounds of the formula (VI) are reacted in an inert solvent inthe presence of a base with a compound of the formula (XI)

in which R¹¹ has the meaning indicated above,to give compounds of the formula (X-B)

in which Ar, D, T, R¹, R³ and R¹¹ each have the meanings indicatedabove,then the ester group T in the compounds of the formula (X-A) or (X-B) iseliminated by methods known per se to give the carboxylic acids of theformula (XII)

in which Ar, D, R¹, R² and R³ each have the meanings indicated above,then converted with 1,1′-carbonyldiimidazole into the imidazolides ofthe formula (XIII)

in which Ar, D, R¹, R² and R³ each have the meanings indicated above,and the latter are then reacted in an inert solvent, where appropriatein the presence of an auxiliary base, with ammonia to give the amides ofthe formula (I),and where appropriate the compounds of the formula (I) are separated bymethods known to the skilled worker into their enantiomers and/ordiastereomers, and/or converted with the appropriate (i) solvents and/or(ii) bases or acids into the solvates, salts and/or solvates of thesalts thereof.

The process sequence (II)+(III)→(IV) and (IV)+(V)→(VI) can also becarried out in one stage as 3-component reaction (II)+(III)+(V)→(VI)without isolating the intermediate (IV).

Process steps (II)+(III)→(IV) and (IV)+(V)→(VI) or (II)+(III)+(V)→(VI)are generally carried out in an inert solvent in a temperature rangefrom +20° C. to the boiling point of the solvent under atmosphericpressure.

Inert solvents suitable for this purpose are for example alcohols suchas methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, halohydrocarbons such as dichloromethane,trichloromethane, tetrachloromethane, trichloroethane or1,2-dichloroethane, or other solvents such as acetonitrile,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hexane, benzene, toluene,chlorobenzene, pyridine or glacial acetic acid. The reactions arepreferably carried out in dichloro-methane, toluene, ethanol orisopropanol at the respective reflux temperature under atmosphericpressure.

Said reactions can where appropriate advantageously take place in thepresence of an acid, of an acid/base combination and/or of a dehydratingagent such as, for example, molecular sieves. Examples of suitable acidsare acetic acid, trifluoroacetic acid, methanesulfonic acid orp-toluenesulfonic acid; suitable bases are in particular piperidine orpyridine [for the synthesis of 1,4-dihydropyridines, compare also D. M.Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223-243; H. Meier et al.,Liebigs Ann. Chem. 1977, 1888; H. Meier et al., ibid. 1977, 1895; H.Meier et al., ibid. 1976, 1762; F. Bossert et al., Angew. Chem. 1981,93, 755].

Inert solvents for process steps (VI)+(VII)→(X-A), (VI)+(VIII)→(X-A) and(VI)+(XI)→(X-B) are for example ethers such as diethyl ether, methyltert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene,xylene, hexane, cyclohexane or petroleum fractions, halohydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane,trichloroethylene, chlorobenzene or chlorotoluene, or other solventssuch as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridineor acetonitrile. It is likewise possible to use mixtures of saidsolvents. Preference is given to the use of tetrahydrofuran ordimethylformamide in process step (VI)+(VII)→(X-A), of dichloromethanein process step (VI)+(VIII)→(X-A), and of pyridine in process step(VI)+(XI)→(X-B).

Process variant (VI)+(IX)→(X-A) is preferably carried out with a largeexcess of orthoformic ester in dimethylformamide or without addition ofa further solvent; strong inorganic acids such as sulfuric acid forexample are advantageous as reaction catalyst [compare for example I. I.Barabanov et al., Russ. Chem. Bl. 47 (11), 2256-2261 (1998)].

Bases suitable for process step (VI)+(VII)→(X-A) are in particularalkali metal or alkaline earth metal carbonates such as lithium, sodium,potassium, calcium or cesium carbonate, alkali metal hydrides such assodium or potassium hydride, amides such as lithium, sodium or potassiumbis(trimethylsilyl)amide or lithium diisopropylamide, organometalliccompounds such as butyllithium or phenyllithium, or else phosphazenebases such as, for example, P2-t-Bu or P4-t-Bu [so-called “Schwesingerbases”, compare R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed.Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837(1991)]. Sodium hydride or the phosphazene base P4-t-Bu is preferablyused.

Bases suitable for process step (VI)+(XI)→(X-B) are in particular alkalimetal or alkaline earth metal carbonates such as lithium, sodium,potassium, calcium or cesium carbonate, alkali metal hydrides such assodium or potassium hydride, organometallic compounds such asbutyllithium or phenyllithium, or organic amines such as triethylamine,N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine,pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) or 1,4-diazabicycl[2.2.2]octane (DABCO®). Pyridine is preferably used and simultaneouslyalso serves as solvent.

Process step (VI)+(VIII)→(X-A) is generally carried out without additionof a base.

The reactions (VI)+(VII)→(X-A), (VI)+(VIII)→(X-A) and (VI)+(XI)→(X-B)generally take place in a temperature range from −20° C. to +100° C.,preferably at 0° C. to +60° C.; process variant (VI)+(IX)→(X-A) isordinarily carried out in a temperature range from +100° C. to +150° C.The reactions can be carried out under atmospheric, elevated or reducedpressure (e.g. from 0.5 to 5 bar); they are generally carried out underatmospheric pressure.

Elimination of the allyl or 2-cyanoethyl ester in process step (X-A) or(X-B)→(XII) takes place by known methods customary in the literature. Inthe case of the 2-cyanoethyl ester, an aqueous solution of an alkalimetal hydroxide such as, for example, sodium or potassium hydroxidesolution is preferably employed for this purpose. The reaction isgenerally carried out using a water-miscible inert cosolvent such as,for example, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, in atemperature range from 0° C. to +40° C. In the case of the allyl ester,the elimination preferably takes place with the aid of Wilkinson'scatalyst [tris(triphenylphosphine)rhodium(I) chloride] in awater/alcohol/acetic acid mixture at temperatures from +50° C. to +100°C. [compare for example Moseley, J. D., Tetrahedron Lett. 46, 3179-3181(2005)].

Examples of inert solvents suitable for process step (XII)→(XIII) areethers such as diethyl ether, methyl tert-butyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, halohydrocarbons such as dichloromethane, trichloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane, chlorobenzene orchlorotoluene, or other solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), acetone, acetonitrile or ethyl acetate. It islikewise possible to use mixtures of said solvents. Tetrahydrofuran,dimethylformamide or ethyl acetate is preferably employed. The reactionis ordinarily carried out in a temperature range from 0° to +40° C.

Inert solvents suitable for process step (XIII)→(I) are for examplealcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanolor tert-butanol, ethers such as diethyl ether, methyl tert-butyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldimethyl ether, or other solvents such as N,N-dimethylformamide (DMF),dimethyl sulfoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), acetonitrile or else water. It is likewisepossible to use mixtures of these solvents. Tetrahydrofuran ordimethylformamide is preferably employed.

Suitable as source of ammonia for this reaction are solutions of gaseousammonia in one of the abovementioned solvents, especially in water. Thereaction can where appropriate advantageously be carried out in thepresence of a tertiary amine as auxiliary base, such as, for example,triethylamine, N-methylmorpholine, N-methylpiperidine,N,N-diisopropylethylamine or 4-N,N-dimethylaminopyridine. The reactiongenerally takes place in a temperature range from +20° C. to +120° C.,preferably at +50° C. to +100° C.

The compounds of the formula (II) are commercially available, known fromthe literature or can be prepared in analogy to processes known from theliterature (compare reaction schemes 1-7 hereinafter). The compounds ofthe formulae (III), (VII), (VIII), (IX) and (XI) are in many casescommercially available, known from the literature or can be prepared bymethods known from the literature.

The compounds of the formula (V) are described in the literature or canbe obtained in analogy to processes known from the literature [comparefor example T. Searls, L. W. McLaughlin, Tetrahedron 55, 11985-11996(1999); D. McNamara, P. D. Cook, J. Med. Chem. 30, 340-347 (1987); S,Nesnow, C. Heidelberger, J. Heterocycl. Chem. 12, 941-944 (1975); N. C.Hung, E. Bisagni, Synthesis 1984, 765-766; Z. Foldi et al., Chem. Ber.75 (7), 755-763 (1942); G. W. Kenner et al., J. Chem. Soc., 388 (1943)].

It is possible where appropriate for separation of the enantiomersand/or diastereomers to take place at the stage of the intermediates(VI), (X-A), (X-B) or (XII), which are then subjected separately to thesubsequent reactions.

Preparation of the Compounds of the Invention can be Illustrated by theFollowing Synthesis Schemes:

The compounds of the invention act as antagonists of themineralocorticoid receptor and show a valuable range of pharmacologicaleffects which could not have been predicted. They are therefore suitablefor use as medicaments for the treatment and/or prophylaxis of diseasesin humans and animals.

The compounds of the invention are suitable for the prophylaxis and/ortreatment of various disorders and disease-related conditions,especially of disorders which are characterized either by an elevationof the plasma aldosterone concentration or by a change in the plasmaaldosterone concentration relative to the plasma renin concentration, orare associated with these changes. Examples which may be mentioned are:idiopathic primary hyperaldosteronism, hyperaldosteronism associatedwith adrenal hyperplasia, adrenal adenomas and/or adrenal carcinomas,hyperaldosteronism associated with cirrhosis of the liver,hyperaldosteronism associated with heart failure, and (relative)hyperaldosteronism associated with essential hypertension.

The compounds of the invention are also suitable, because of theirmechanism of action, for the prophylaxis of sudden cardiac death inpatients at increased risk of dying of sudden cardiac death. These arein particular patients suffering for example from one of the followingdisorders: primary and secondary hypertension, hypertensive heartdisease with or without congestive heart failure, therapy-resistanthypertension, acute and chronic heart failure, coronary heart disease,stable and unstable angina pectoris, myocardial ischemia, myocardialinfarction, dilated cardiomyopathies, congenital primarycardiomyopathies such as, for example, Brugada syndrome,cardiomyopathies induced by Chagas' disease, shock, arteriosclerosis,atrial and ventricular arrhythmia, transient and ischemic attacks,stroke, inflammatory cardiovascular disorders, peripheral and cardiacvascular disorders, peripheral blood flow disturbances, arterialocclusive diseases such as intermittent claudication, asymptomaticleft-ventricular dysfunction, myocarditis, hypertrophic alterations ofthe heart, pulmonary hypertension, spasms of the coronary arteries andperipheral arteries, thromboses, thromboembolic disorders, andvasculitis.

The compounds of the invention can additionally be used for theprophylaxis and/or treatment of edema formation, such as, for example,pulmonary edema, renal edema or heart failure-related edema, and ofrestenoses such as following thrombolysis therapies, percutaneoustransluminal angioplasties (PTA) and coronary angioplasties (PTCA),heart transplants and bypass operations.

The compounds of the invention are further suitable for use aspotassium-sparing diuretic and for electrolyte disturbances such as, forexample, hypercalcemia, hypernatremia or hypokalemia.

The compounds of the invention are likewise suitable for the treatmentof renal disorders such as acute and chronic renal failure, hypertensivekidney disease, arteriosclerotic nephritis (chronic and interstitial),nephrosclerosis, chronic renal failure and cystic renal disorders, forthe prevention of kidney damage which may be caused for example byimmunosuppressants such as cyclosporin A in association with organtransplants, and for renal cancer.

The compounds of the invention can additionally be employed for theprophylaxis and/or treatment of diabetes mellitus and diabetic sequelaesuch as, for example, neuropathy and nephropathy.

The compounds of the invention can further be used for the prophylaxisand/or treatment of microalbuminuria, for example caused by diabetesmellitus or high blood pressure, and of proteinuria.

The compounds of the invention are also suitable for the prophylaxisand/or treatment of disorders associated either with an increase in theplasma glucocorticoid concentration or with a local increase in theconcentration of glucocorticoids in tissue (e.g. of the heart). Exampleswhich may be mentioned are: adrenal dysfunctions leading tooverproduction of glucocorticoids (Cushing's syndrome), adrenocorticaltumors with resulting overproduction of glucocorticoids, and pituitarytumors which autonomously produce ACTH (adrenocorticotropic hormone) andthus lead to adrenal hyperplasias with resulting Cushing's disease.

The compounds of the invention can additionally be employed for theprophylaxis and/or treatment of obesity, of metabolic syndrome and ofobstructive sleep apnea.

The compounds of the invention can further be used for the prophylaxisand/or treatment of inflammatory disorders caused for example byviruses, spirochetes, fungi, bacteria or mycobacteria, and ofinflammatory disorders of unknown etiology, such as polyarthritis, lupuserythematosus, peri- or polyarteritis, dermatomyositis, scleroderma andsarcoidosis.

The compounds of the invention can further be employed for the treatmentof central nervous disorders such as depressions, anxiety states andchronic pain, especially migraine, and for neurodegenerative disorderssuch as Alzheimer's disease and Parkinson's syndrome.

The compounds of the invention are also suitable for the prophylaxisand/or treatment of vascular damage, e.g. following procedures such aspercutaneous transluminal coronary angioplasty (PTCA), implantations ofstents, coronary angioscopy, reocclusion or restenosis following bypassoperations, and for endothelial dysfunction, for Raynaud's disease, forthromboangiitis obliterans (Buerger's syndrome) and for tinnitussyndrome.

The present invention further relates to the use of the compounds of theinvention for the treatment and/or prevention of disorders, especiallyof the aforementioned disorders.

The present invention further relates to the use of the compounds of theinvention for the manufacture of a medicament for the treatment and/orprevention of disorders, especially of the aforementioned disorders.

The present invention further relates to a method for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders, by using an effective amount of at least one of the compoundsof the invention.

The compounds of the invention can be employed alone or, if required, incombination with other active ingredients. The present invention furtherrelates to medicaments comprising at least one of the compounds of theinvention and one or more further active ingredients, especially for thetreatment and/or prevention of the aforementioned disorders. Suitableactive ingredients for combinations are by way of example andpreferably:

-   -   active ingredients which lower blood pressure, for example and        preferably from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, endothelin antagonists, renin        inhibitors, alpha-receptor blockers, beta-receptor blockers and        Rho kinase inhibitors;    -   diuretics, especially loop diuretics, and thiazides and        thiazide-like diuretics;    -   agents having an antithrombotic effect, for example and        preferably from the group of platelet aggregation inhibitors, of        anticoagulants or of profibrinolytic substances;    -   active ingredients which alter lipid metabolism, for example and        preferably from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors such as by way of example and        preferably HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,        PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol        absorption inhibitors, lipase inhibitors, polymeric bile        adsorbents, bile acid reabsorption inhibitors and lipoprotein(a)        antagonists;    -   organic nitrates and NO donors such as, for example, sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds having a positive inotropic effect, such as, for        example, cardiac glycosides (digoxin), beta-adrenergic and        dopaminergic agonists such as isoproterenol, adrenaline,        noradrenaline, dopamine and dobutamine;    -   compounds which inhibit the degradation of cyclic guanosine        monophosphate (cGMP) and/or cyclic adenosine monophosphate        (cAMP), such as, for example, inhibitors of phosphodiesterases        (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5 inhibitors such as        sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors such        as aminone and milrinone;    -   natriuretic peptides such as, for example, atrial natriuretic        peptide (ANP, anaritide), B-type natriuretic peptide or brain        natriuretic peptide (BNP, nesiritide), C-type natriuretic        peptide (CNP) and urodilatin;    -   calcium sensitizers such as by way of example and preferably        levosimendan;    -   NO-independent but heme-dependent stimulators of guanylate        cyclase such as in particular the compounds described in WO        00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;    -   NO- and heme-independent activators of guanylate cyclase, such        as in particular the compounds described in WO 01/19355, WO        01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO        02/070510;    -   inhibitors of human neutrophil elastase (HNE), such as, for        example, sivelestat or DX-890 (reltran);    -   compounds which inhibit the signal transduction cascade, such        as, for example, tyrosine kinase inhibitors, in particular        sorafenib, imatinib, gefitinib and erlotinib; and/or    -   compounds which influence the energy metabolism of the heart,        such as by way of example and preferably etomoxir,        dichloroacetate, ranolazine or trimetazidine.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a diuretic such as by wayof example and preferably furosemide, bumetanide, torsemide,bendroflumethiazide, chlorthiazide, hydrochlorthiazide,hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide,chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide,dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol,amiloride or triamterene.

Agents which lower blood pressure preferably mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, Rho kinase inhibitors, and diuretics.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a calcium antagonist suchas by way of example and preferably nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an angiotensin AIIantagonist such as by way of example and preferably losartan,candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACE inhibitor such asby way of example and preferably enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an endothelin antagonistsuch as by way of example and preferably bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a renin inhibitor such asby way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676,SPP-800 or SPP-1148.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an alpha-1 receptorblocker such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a beta-receptor blockersuch as by way of example and preferably propranolol, atenolol, timolol,pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol,nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol,celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol,adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a Rho kinase inhibitorsuch as by way of example and preferably fasudil, Y-27632, SLx-2119,BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

Agents having an antithrombotic effect (antithrombotics) preferably meancompounds from the group of platelet aggregation inhibitors, ofanticoagulants or of profibrinolytic substances.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a platelet aggregationinhibitor such as by way of example and preferably aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thrombin inhibitor suchas by way of example and preferably ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a GPIIb/IIIa antagonistsuch as by way of example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a factor Xa inhibitorsuch as by way of example and preferably rivaroxaban (BAY 59-7939),DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux,idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021,DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a vitamin K antagonistsuch as by way of example and preferably coumarin.

Agents which alter lipid metabolism preferably mean compounds from thegroup of CETP inhibitors, thyroid receptor agonists, cholesterolsynthesis inhibitors such as HMG-CoA reductase inhibitors or squalenesynthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors, lipase inhibitors and lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a CETP inhibitor such asby way of example and preferably torcetrapib (CP-529 414), JJT-705, BAY60-5521, BAY 78-7499 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a thyroid receptoragonist such as by way of example and preferably D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins such as by way of example andpreferably lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a squalene synthesisinhibitor such as by way of example and preferably BMS-188494 orTAK-475.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an ACAT inhibitor such asby way of example and preferably avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with an MTP inhibitor such asby way of example and preferably implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a PPAR-gamma agonist suchas by way of example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a PPAR-delta agonist suchas by way of example and preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a cholesterol absorptioninhibitor such as by way of example and preferably ezetimibe, tiquesideor pamaqueside.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipase inhibitor suchas by way of example and preferably orlistat.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a polymeric bileadsorbent such as by way of example and preferably cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a bile acid reabsorptioninhibitor such as by way of example and preferably ASBT (=IBAT)inhibitors such as, for example, AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of theinvention are administered in combination with a lipoprotein(a)antagonist such as by way of example and preferably gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further relates to medicaments which comprise atleast one compound of the invention, normally together with one or moreinert, non-toxic, pharmaceutically suitable excipients, and to the usethereof for the aforementioned purposes.

The compounds of the invention may have systemic and/or local effects.For this purpose, they can be administered in a suitable way such as,for example, by the oral, parenteral, pulmonary, nasal, sublingual,lingual, buccal, rectal, dermal, transdermal, conjunctival or otic routeor as implant or stent.

The compounds of the invention can be administered in administrationforms suitable for these administration routes.

Suitable for oral administration are administration forms which functionaccording to the prior art and deliver the compounds of the inventionrapidly and/or in a modified manner, and which contain the compounds ofthe invention in crystalline and/or amorphized and/or dissolved form,such as, for example, tablets (uncoated and coated tablets, for examplehaving coatings which are resistant to gastric juice or are insoluble ordissolve with a delay and control the release of the compound of theinvention), tablets which disintegrate rapidly in the mouth, orfilms/wafers, films/lyophilizates, capsules (for example hard or softgelatin capsules), sugar-coated tablets, granules, pellets, powders,emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of an absorption (e.g intramuscular,subcutaneous, intracutaneous, percutaneous, or intraperitoneal).Administration forms suitable for parenteral administration are, interalia, preparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

Suitable for the other routes of administration are, for example,pharmaceutical forms for inhalation (inter alia powder inhalers,nebulizers), nasal drops, solutions, sprays; tablets for lingual,sublingual or buccal administration, films/wafers or capsules,suppositories, preparations for the ears and eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (for examplepatches), milk, pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration are preferred, especially oral andintravenous administration.

The compounds of the invention can be converted into the statedadministration forms. This can take place in a manner known per se bymixing with inert, non-toxic, pharmaceutically suitable excipients.These excipients include inter alia carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as, for example,ascorbic acid), colorings (e.g. inorganic pigments such as, for example,iron oxides) and masking flavors and/or odors.

It has generally proved to be advantageous on parenteral administrationto administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01to 0.5 mg/kg of body weight per day to achieve effective results. Onoral administration, the dosage is about 0.01 to 100 mg/kg, preferablyabout 0.01 to 20 mg/kg, and very particularly preferably about 0.1 to 10mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, in particular as a function of body weight,administration route, individual response to the active ingredient, typeof preparation and time or interval over which administration takesplace. Thus, in some cases it may be sufficient to make do with lessthan the aforementioned minimum amount, whereas in other cases the upperlimit mentioned must be exceeded. Where relatively large amounts areadministered, it may be advisable to distribute these in a plurality ofsingle doses over the day.

The following exemplary embodiments illustrate the invention. Theinvention is not restricted to the examples.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data of liquid/liquidsolutions are based in each case on the volume.

A. EXAMPLES

Abbreviations and acronyms: abs. absolute AIBN2,2′-azobis-2-methylpropanenitrile aq. aqueous, aqueous solution cat.catalytic CI chemical ionization (in MS) conc. concentrated d day(s) DME1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide eeenantiomeric excess EI electron impact ionization (in MS) entenantiomer/enantiopure eq equivalent(s) ESI electrospray ionization (inMS) GC-MS coupled gas chromatography-mass spectrometry h hour(s) HPLChigh pressure, high performance liquid chromatography LC-MS coupledliquid chromatography-mass spectrometry min minute(s) MPLC mediumpressure liquid chromatography MS mass spectrometry NMR nuclear magneticresonance spectrometry Ph phenyl R_(f) retention index (in TLC) R_(t)retention time (in HPLC) RT room temperature THF tetrahydrofuran TLCthin-layer chromatography v/v volume-to-volume ratio (of a solution) wt% percent by weightLC-MS and GC-MS Methods:Method 1 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2μ, Hydro-RP Mercury 20 mm×4 mm; eluentA: 1 l of water+0.5 ml of 50% formic acid, eluent B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient 0.0 min 90% A→2.5 min30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm

Method 2 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Synergi 2μ, Hydro-RP Mercury 20 mm×4 mm; eluent A: 1 l ofwater+0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of50% formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 208-400 nm

Method 3 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3μ, 30 mm×3.00 mm; eluent A: 1 l ofwater+0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of50% formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0 min/4.5 min 2 ml/min;oven: 50° C.; UV detection: 210 nm

Method 4 (LC-MS):

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3μ, 20 mm×4 mm; eluent A: 1 l of water+0.5ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9 min 30% A→3.1min 10% A→5.5 min 10% A; oven: 50° C.; flow rate: 0.8 ml/min; UVdetection: 210 nm.

Method 5 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35MS, 30 m×250μm×0.25 μm; constant flow with helium: 0.88 ml/min; oven: 60° C.; inlet:250° C.; gradient: 60° C. (halt for 0.30 min), 50° C./min→120° C., 16°C./min→250° C., 30° C./min→300° C. (halt for 1.7 min).

Method 6 (LC-MS):

MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Onyx Monolithic C18, 100 mm×3 mm; eluent A: 1 lof water+0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 mlof 50% formic acid; gradient 0.0 min 90% A→2 min 65% A→4.5 min 5% A→6min 5% A; flow rate: 2 ml/min; oven: 40° C.; UV detection: 210 nm

Method 7 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Onyx Monolithic C18, 100 mm×3 mm; eluent A: 1 l of water+0.5ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50%formic acid; gradient: 0.0 min 90% A→2 min 65% A→4.5 min 5% A→6 min 5%A; flow rate: 2 ml/min; oven: 40° C.; UV detection: 208-400 nm

Method 8 (LC-MS):

Instrument type: Micromass ZQ; instrument type: Waters Alliance 2795:column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm×4 mm; eluentA: 1 l of water+0.5 ml of 50% formic acid, eluent B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient 0.0 min 90% A→0.1 min90% A→3.0 min 5% A→4.0 min 5% A→4.01 min 90% A; flow: 2 ml/min; oven:50° C.; UV detection: 210 nm

Method 9 (LC-MS):

Instrument: Micromass Quattro Premier with Waters HPLC Acquity; column:Thermo Hypersil GOLD 1.9μ, 50 nm×1 nm; eluent A: 1 l water+0.5 ml 50%formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% formic acid;gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A; flow0.33 ml/min; oven: 50° C.; UV detection: 210 nm.

Starting Compounds and Intermediates Example 1A1-[2-(allyloxy)phenyl]ethanone

542 g (3.9 mol) of 2-hydroxyacetophenone are heated to reflux with 592 g(4.9 mol) of allyl bromide, 1000 g (7.2 mol) of potassium carbonate and13.2 g (79 mmol) of potassium iodide in 2.4 liters of acetone for 24 h.Cooling to room temperature is followed by filtration, and the solventis removed in vacuo. The residue is dissolved in toluene and washed with10% strength sodium hydroxide solution and water. Concentration resultsin 689 g (98% of theory) of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=2.68 (s, 3H), 4.68 (dd, 2H), 5.89 (dd, 2H),6.09 (m, 1H), 6.99 (dd, 2H), 7.44 (m, 1H), 7.71 (d, 1H).

Example 2A 1-(3-allyl-2-hydroxyphenyl)ethanone

160 g (0.9 mol) of 1-[2-(allyloxy)phenyl]ethanone are stirred in a metalbath at 230-240° C. for 4 h. After cooling to room temperature, theproduct is distilled in a thin-film evaporator at 140° C. and 0.4 mbar.155 g (97% of theory) of the title compound are obtained.

¹H-NMR (300 MHz, CDCl₃): δ=2.68 (s, 3H), 3.44 (d, 2H), 5.09 (m, 2H),6.01 (m, 1H), 6.85 (t, 1H), 7.38 (dd, 1H), 7.62 (dd, 1H), 12.61 (s, 1H).

Example 3A 1-{2-Hydroxy-3-[(1E)-prop-1-en-1-yl]phenyl}ethanone

40 g (227 mmol) of 1-(3-allyl-2-hydroxyphenyl)ethanone are dissolved in120 ml of toluene, and 2.17 g (5.6 mmol) ofbis(benzonitrile)dichloropalladium(II) are added. The reaction mixtureis heated at 120° C. overnight. Cooling to room temperature is followedby filtration through kieselguhr, and the solvent is removed in vacuo.20.9 g (95% of theory) of the title compound are obtained and arereacted without further purification in the next stage.

LC-MS (method 1): R_(t)=2.36 min; [M+H]⁺=177

¹H-NMR (300 MHz, CDCl₃): δ=1.91 (dd, 3H), 2.63 (s, 3H), 6.32 (m, 1H),6.73 (dd, 1H), 6.85 (t, 1H), 7.59 (m, 2H), 12.74 (s, 1H).

Example 4A 2-Methyl-8-[(1E)-prop-1-en-1-yl]-4H-chromen-4-one

12.52 g (313.2 mmol) of 60% sodium hydride (suspension in mineral oil)are introduced into 300 ml of absolute THF under argon at 10° C. 18.4 g(104.4 mmol) of 1-{2-hydroxy-3-[(1E)-prop-1-en-1-yl]phenyl}ethanone areslowly added dropwise to the suspension. After 15 min, 9 g (114.9 mmol)of acetyl chloride are added. The reaction mixture is stirred at roomtemperature overnight. Hydrolysis is carried out with 300 ml of water,and the mixture is extracted several times with ethylacetate. Washing ofthe organic phase with saturated sodium chloride solution is followed bydrying over sodium sulfate. The solvent is then removed in vacuo. Theresidue is taken up in 200 ml of methanol and heated with 50 ml of 20%strength hydrochloric acid at 80° C. for 30 min. The solvent is thenremoved in vacuo, and the residue is mixed with 400 ml of water. Severalextractions with dichloromethane are carried out. After the organicphase has been dried over magnesium sulfate, the solvent is removed invacuo and the residue is purified by column chromatography (mobilephase: dichloromethane/methanol 98:2). 10.5 g (50.2% of theory) of thetitle compound are obtained as a yellow oil.

LC-MS (method 2): R_(t)=2.07 min; [M+H]⁺=201

¹H-NMR (300 MHz, CDCl₃): δ=1.98 (dd, 3H), 2.43 (s, 3H), 6.18 (s, 1H),6.40 (m, 1H), 6.85 (dd, 1H), 7.31 (t, 1H), 7.72 (dd, 1H), 8.05 (dd, 1H).

Example 5A 2-Methyl-4-oxo-4H-chromene-8-carbaldehyde

18.5 g (62.8 mmol) of 2-methyl-8-[(1E)-prop-1-en-1-yl]-4H-chromen-4-oneare dissolved in 400 ml of dichloromethane and cooled to −60° C. Ozoneis passed into the reaction solution for 30 min Dimethyl sulfide is thenadded to the reaction mixture. After warming to room temperature, thesolvent is removed in vacuo and the residue is slurried in a littlemethanol. The solid remaining after filtration is recrystallized fromdiethyl ether. 9.1 g (77.4% of theory) of the title compound areobtained.

LC-MS (method 1): R_(t)=1.31 min; [M+H]⁺=189

¹H-NMR (300 MHz, CDCl₃): δ=2.48 (s, 3H), 6.27 (s, 1H), 7.51 (m, 1H),8.21 (dd, 1H), 8.46 (dd, 1H), 10.67 (s, 1H).

Example 6A 4-Bromo-2-(trifluoromethoxy)benzaldehyde

20.00 g (54.51 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene aredissolved in 200 ml of THF and cooled to −78° C. Then 26.16 ml (65.41mmol) of a 2.5 M solution of n-butyllithium in hexane are addeddropwise. The mixture is stirred for 30 min and then 14.43 g (125.37mmol) of N-formylmorpholine are metered in. After complete conversion isdetected (TLC check), solvolysis is carried out at −78° C. withisopropanol. Warming to room temperature is followed by addition ofwater and extraction twice with dichloromethane. The combined organicphases are washed with saturated sodium chloride solution and dried withsodium sulfate, and the solvent is distilled out under reduced pressure.The residue is purified by column chromatography (silica gel, mobilephase: cyclohexane/ethyl acetate 5:1). 11.43 g (78% of theory) of thetitle compound are obtained.

GC-MS (method 5): R_(t)=4.24 min; MS (Elpos): m/z=270 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=7.85-7.92 (m, 3H), 10.20 (s, 1H).

Example 7A 4-Formyl-3-(trifluoromethoxy)benzonitrile

10.63 g (39.51 mmol) of 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.43 g(29.24 mmol) of zinc cyanide and 1.37 g (1.19 mmol) oftetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of DMF.The reaction mixture is then reacted in several portions in a singlemode microwave (Emrys Optimizer, 5 min at 220° C.). The combinedmixtures are mixed with water and extracted twice with toluene. Thecombined organic phases are washed with saturated sodium chloridesolution and dried with sodium sulfate, and then the solvent is removedin a rotary evaporator. The residue is purified by column chromatography(silica gel, mobile phase: cyclohexane/ethyl acetate 10:1). 3.32 g (78%of theory) of the title compound are obtained with a purity of 80%(according to LC-MS).

MS (Elpos): m/z=215 [M]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=7.85-7.91 (m, 3H), 10.20 (s, 1H).

Example 8A 4-Cyano-2-methoxyphenyl trifluoromethanesulfonate

24 ml (141 mmol) of trifluoromethanesulfonic anhydride are slowly addeddropwise to a solution of 20 g (134 mmol) of4-hydroxy-3-methoxybenzonitrile in pyridine (80 ml), keeping thereaction temperature below 25° C. with the aid of an ice bath. Thesuspension is then stirred at RT for 1 h. Ice-water (400 ml) is added,and the suspension is stirred further until room temperature is reached.It is then filtered, the solid is dissolved in ethyl acetate, and thesolution is washed with saturated sodium chloride solution. The organicphase is dried over magnesium sulfate and concentrated. 37.13 g (92% oftheory) of the title compound are obtained as a white solid.

LC-MS (method 3): R_(t)=2.54 min; MS (Elpos): m/z=282 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.97 (s, 3H), 7.60 (dd, 1H), 7.71 (d, 1H),7.92 (d, 1H).

Example 9A tert-Butyl (2E)-3-(4-cyano-2-methoxyphenyl)acrylate

4 g (5.7 mmol) of bis(triphenylphosphine)palladium(II) chloride areadded to a degassed solution of 37.13 g (132 mmol) of4-cyano-2-methoxyphenyl trifluoromethanesulfonate, 35 ml (245 mmol) oftert-butyl acrylate and 90 ml (645 mmol) of triethylamine in DMF (250ml). The solution is stirred at 100° C. under a protective gasatmosphere for 24 h. Ice-water (1000 ml) is then added, and thesuspension is extracted with ethyl acetate (3×100 ml). The organic phaseis washed with saturated sodium chloride solution, dried over magnesiumsulfate and concentrated. The residue is purified by columnchromatography (silica gel, mobile phase: cyclohexane/ethyl acetate10:1). 24.6 g (72% of theory) of the title compound are obtained as awhite solid.

LC-MS (method 1): R_(t)=2.59 min; MS (Elpos): m/z=260 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.48 (s, 9H), 3.93 (s, 3H), 6.65 (d, 1H),7.42 (d, 1H), 7.58 (s, 1H), 7.74 (d, 1H), 7.89 (d, 1H).

Example 10A 4-Formyl-3-methoxybenzonitrile

79 g (370 mmol) of sodium metaperiodate are added in portions to avigorously stirred solution of 48 g (185 mmol) of tert-butyl(2E)-3-(4-cyano-2-methoxyphenyl)acrylate, 207 mg (0.81 mmol) of osmiumtetroxide and 1.4 g (6.14 mmol) of benzyltriethylammonium chloride in750 ml of water/THF (2:1), keeping the reaction temperature below 30° C.The solution is stirred at RT for a further 1 h. Water (2000 ml) isadded and the mixture is then filtered. The remaining solid is dissolvedin ethyl acetate, and the solution is washed with saturated sodiumchloride solution. The organic phase is dried over magnesium sulfate andconcentrated. The residue is stirred with petroleum ether. 21.18 g (71%of theory) of the title compound are obtained as a white solid.

LC-MS (method 3): R_(t)=1.87 min; MS (Elpos): m/z=162 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H),7.81 (d, 1H), 10.37 (s, 1H).

Example 11A 4-Formyl-3-hydroxybenzonitrile

100 ml of a boron tribromide solution in dichloromethane (1 M, 100 mmol)are added dropwise to a solution of 8 g (49.64 mmol) of4-formyl-3-methoxybenzonitrile in 80 ml of anhydrous dichloromethane at−78° C. under an argon atmosphere. The reaction mixture is stirred at RTuntil the precursor has completely reacted (about 5 days). The reactionsolution is then neutralized at 0° C. with saturated sodium bicarbonatesolution. The phases are separated and the organic phase is washed withsaturated sodium chloride solution, dried over magnesium sulfate andconcentrated. The residue is purified by column chromatography on silicagel (mobile phase: cyclohexane/ethyl acetate 3:1). 4.5 g (61% of theory)of the title compound are obtained as a yellow solid.

LC-MS (method 1): R_(t)=1.38 min; [M−H]⁻=146

¹H-NMR (300 MHz, CDCl₃): δ=7.38 (d, 1H), 7.38 (s, 1H), 7.77 (d, 1H),10.33 (s, 1H), 11.38 (s, 1H).

Example 12A 5-Cyano-2-formylphenyl trifluoromethanesulfonate

2.4 ml (14.27 mmol) of trifluoromethanesulfonic anhydride are addeddropwise to a solution of 2 g (13.59 mmol) of4-formyl-3-hydroxybenzonitrile and 2.5 ml (14.27 mmol) ofN,N-diisopropyl-ethylamine in 37 ml of anhydrous dichloromethane at 0°C. under an argon atmosphere. The reaction mixture is stirred at RT for1 h, then diluted with 70 ml of dichloromethane and washed successivelywith 1 M hydrochloric acid, saturated sodium bicarbonate solution andsaturated sodium chloride solution. The organic solution is dried overmagnesium sulfate and concentrated. The residue is purified by columnchromatography on silica gel (mobile phase: cyclohexane/ethyl acetate7:1). 2.36 g (62% of theory) of the title compound are obtained as awhite solid.

LC-MS (method 3): R_(t)=2.34 min; [M+H]⁺=280

¹H-NMR (300 MHz, CDCl₃): δ=8.27 (m, 2H), 8.33 (s, 1H), 10.13 (s, 1H).

Example 13A 4-Formyl-3-vinylbenzonitrile

125 mg (0.18 mmol) of bis(triphenylphosphine)palladium(II) chloride areadded to a solution of 1 g (3.58 mmol) of 5-cyano-2-formylphenyltrifluoromethanesulfonate and 1.15 ml (3.94 mmol) oftri-n-butylvinylstannane in 6 ml of anhydrous and degassed DMF under anargon atmosphere. The reaction mixture is then stirred at 80° C. for 90min. Subsequently, 100 ml of 10% strength potassium fluoride solutionare added, and the mixture is stirred at RT for 1 h. The suspension isextracted three times with 20 ml of ethyl acetate each time, and thecombined organic phases are washed successively with saturated sodiumbicarbonate solution and saturated sodium chloride solution. The organicsolution is dried over magnesium sulfate and concentrated. The residue(0.6 g) is employed without further purification in the next stage.

GC-MS (method 5): R_(t)=5.02 min; [M]⁺=157

¹H-NMR (300 MHz, CDCl₃): δ=5.62 (d, 1H), 6.05 (d, 1H), 7.58 (dd, 1H),7.95 (d, 1H), 8.00 (d, 1H), 8.24 (s, 1H), 10.32 (s, 1H).

Example 14A 3-Ethyl-4-formylbenzonitrile

A solution of 1.3 g (8.27 mmol) of 4-formyl-3-vinylbenzonitrile in 35 mlof ethanol is mixed with 880 mg of 10% palladium on carbon andvigorously stirred under a hydrogen atmosphere for 2 h. The suspensionis filtered through a layer of kieselguhr, the residue is washed withethanol, and the filtrate is concentrated. The residue (890 mg) isemployed without further purification in the following stage.

¹H-NMR (300 MHz, CDCl₃): δ=1.2 (t, 1H), 3.07 (q, 2H), 7.88 (d, 1H), 7.90(s, 1H), 7.97 (d, 1H), 10.32 (s, 1H).

Example 15A Methyl 4-cyano-2-fluorobenzoate

13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300ml of acetone. Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08ml (95.9 mmol) of dimethyl sulfate are successively added. The mixtureis stirred at reflux temperature for 20 h. The reaction mixture is thenmixed with 300 ml of water and the acetone is removed in a rotaryevaporator. Several extractions with dichloromethane are carried out.The combined organic phases are washed with saturated sodium chloridesolution and dried over sodium sulfate. The solvent is then removed invacuo. The remaining solid is used further without further purification.16.1 g (84% of theory) of the title compound are obtained as a colorlesssolid.

GC-MS (method 5): R_(t)=6.23 min; [M]⁺ (Elpos): m/z=179

¹H-NMR (300 MHz, DMSO-d₆): δ=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m,2H).

Example 16A 3-Fluoro-4-(hydroxymethyl)benzonitrile

16.10 g (89.9 mmol) of methyl 4-cyano-2-fluorobenzoate are dissolved in150 ml of methanol. Then 3.40 g (89.9 mmol) of sodium borohydride areadded in portions. After the reaction has taken place (TLC check), themixture is adjusted to pH 3 with dilute hydrochloric acid and extractedseveral times with dichloromethane. The combined organic phases arewashed with saturated sodium chloride solution and dried with magnesiumsulfate. The solvent is then removed in vacuo, and the residue ispurified by column chromatography (silica gel, mobile phase:cyclohexane/ethyl acetate 15:1→3:7). 3.70 g (27.2% of theory) of thetitle compound are obtained.

GC-MS (method 5): R_(t)=6.51 min; [M]⁺ (Elpos): m/z=151

¹H-NMR (300 MHz, DMSO-d₆): δ=4.61 (s, 2H), 5.53 (s, 1H), 7.61-7.74 (m,2H), 7.79 (dd, 1H).

Example 17A 3-Fluoro-4-formylbenzonitrile

1.00 g (6.62 mmol) of 3-fluoro-4-(hydroxymethyl)benzonitrile aredissolved in 50 ml of dichloromethane, and 9.20 g (105.9 mmol) ofmanganese(IV) oxide are added. The mixture is stirred at roomtemperature overnight and then filtered through a short kieselguhrcolumn. The solvent is distilled out under reduced pressure, and theresidue is purified by column chromatography (silica gel, mobile phase:dichloromethane). 120 mg (12.1% of theory) of the title compound areobtained.

GC-MS (method 5): R_(t)=5.11 min; [M]⁺ (Elpos): m/z=149

¹H-NMR (300 MHz, DMSO-d₆): δ=7.89 (d, 1H), 8.00 (t, 1H), 8.11 (d, 1H),10.24 (d, 1H).

Example 18A 3-Chloro-4-formylbenzonitrile

25.0 g (164.91 mmol) of 3-chloro-4-methylbenzonitrile are dissolved in150 ml of DMF, and 25.55 g (214.39 mmol) of N,N-dimethylformamidedimethyl acetal are added. The mixture is stirred in an oil bath at atemperature of 140° C. for 20 h and then at 180° C. for 4 h. Thevolatile components are removed in a rotary evaporator, and theremaining residue is directly reacted further.

The crude 3-chloro-4-[2-(dimethylamino)vinyl]benzonitrile obtained inthis way is taken up in 500 ml of THF/water (1:1), and 77.6 g (362.9mmol) of sodium periodate are added. The mixture is stirred at roomtemperature for 18 h, and then the precipitate which has separated outis removed by filtration. The filtrate is mixed with saturated sodiumbicarbonate solution and extracted three times with ethyl acetate. Thecombined organic phases are dried with sodium sulfate, and the solventis removed in a rotary evaporator. The crude product is purified bycolumn chromatography (silica gel, mobile phase: cyclohexane/ethylacetate 7:3). 3.0 g (15% of theory) of the title compound are obtained.

GC-MS (method 5): R_(t)=6.64 min; [M]⁺ (Elpos): m/z=165

¹H-NMR (300 MHz, DMSO-d₆): δ=7.97-8.03 (m, 2H), 8.27 (s, 1H), 10.34 (d,1H).

Example 19A 4-Formyl-1-naphthonitrile

2.50 g (14.95 mmol) of 4-methyl-1-naphthonitrile are dissolved in 40 mlof tetrachloromethane and 3.19 g (17.94 mmol) of N-bromosuccinimide and245 mg (1.50 mmol) of 2,2′-azobis-2-methyl-propanenitrile are added. Themixture is stirred at the reflux temperature overnight. After cooling,the product is filtered off 2.75 g (74.7% of theory) of4-(bromomethyl)-1-naphthonitrile are obtained in a purity of 90% and arereacted without further purification.

2.75 g (11.17 mmol) of the bromide obtained in this way are dissolved in60 ml of acetonitrile, and 2 g of molecular sieves (3 Å) are added. Then1.44 g (12.29 mmol) of N-methylmorpholine N-oxide are added, and themixture is stirred at room temperature overnight. The mixture is thenfiltered through silica gel and the filtrate is concentrated. Theresidue is purified on a Biotage cartridge (40 M) (eluent:isohexane/ethyl acetate 3:1). The product fractions are combined, thesolvent is removed in a rotary evaporator, and the residue is thenstirred with diethyl ether, whereupon crystallization occurs. Theproduct is washed with a little diethyl ether and dried under highvacuum. 254 mg (12.6% of theory) of the title compound are obtained.

LC-MS (method 3): R_(t)=2.27 min; [M+H]⁺(Elpos): m/z=182

¹H-NMR (300 MHz, CDCl₃): δ=7.79-7.87 (m, 2H), 8.05 (d, 1H), 8.09 (d,1H), 8.37 (m, 1H), 9.27 (m, 1H), 10.51 (s, 1H).

Example 20A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

14.63 g (90.81 mmol) of the compound from Example 10A, 10.00 g (90.81mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W.,Tetrahedron 55, 11985-11996 (1999)] and 15.65 g (90.81 mmol) of2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem.Lett. 16, 798-802 (2006)] are dissolved in 300 ml of isopropanol andstirred at the reflux temperature under argon for 3 days. The mixture isthen concentrated and subsequently purified by column chromatography(silica gel; mobile phase: initially ethyl acetate and thendichloromethane/methanol 10:1). The resulting product fractions areconcentrated and then taken up in a little ethyl acetate. Theprecipitated product is filtered off and dried at 40° C. in vacuoovernight. 10.11 g (27% of theory) of the title compound are obtained.

LC-MS (method 6): R_(t)=1.83 min; MS (Elpos): m/z=391 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.27 (s, 3H), 2.79 (m, 2H), 3.75 (s, 3H),3.96-4.14 (m, 2H), 5.19 (s, 1H), 5.87 (d, 1H), 7.10 (d, 1H), 7.23 (dd,1H), 7.30-7.35 (m, 2H), 9.30 (s, 1H), 10.83 (s, 1H).

Example 21A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

10.00 g (25.62 mmol) of the compound from Example 20A are suspended in250 ml of triethyl orthoformate and heated to 130° C. Then, over a totalperiod of 8 hours, 15 drops of concentrated sulfuric acid are added eachhour to the reaction mixture. It is then stirred at the same temperatureovernight. After cooling, excess orthoester is removed in a rotaryevaporator, and the crude product is purified by column chromatography(silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 7.20 g (65%of theory) of the title compound are obtained.

LC-MS (method 6): R_(t)=2.82 min; MS (Elpos): m/z=419 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.12 (t, 3H), 2.33 (s, 3H), 2.77 (m, 2H),3.78 (s, 3H), 3.99-4.13 (m, 4H), 5.37 (s, 1H), 6.48 (d, 1H), 7.25 (dd,1H), 7.29-7.35 (m, 2H), 7.73 (d, 1H), 9.53 (s, 1H).

Example 22A4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

7.20 g (17.21 mmol) of the compound from Example 21A are dissolved in200 ml of 1,2-dimethoxyethane/water (3:1 v/v), mixed with 34.42 ml(34.42 mmol) of 1 N sodium hydroxide solution and stirred at roomtemperature overnight. The mixture is then mixed with 100 ml of diethylether and 100 ml of water, the organic phase is separated off, and theaqueous phase is adjusted to pH 4-5 with 1N hydrochloric acid. Theresulting suspension is stirred for 1 h and the precipitated solid isthen removed by filtration. The precipitate is washed with water and alittle diethyl ether. Drying in vacuo at 40° C. results in 3.57 g (57%of theory) of the title compound.

LC-MS (method 7): R_(t)=2.32 min; MS (Elpos): m/z=366 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.12 (t, 3H), 2.28 (s, 3H), 3.74 (s, 3H),4.07 (m, 2H), 5.33 (s, 1H), 6.44 (d, 1H), 7.23-7.29 (m, 2H), 7.32 (s,1H), 7.70 (d, 1H), 9.25 (s, 1H), 11.34 (s, 1H).

Example 23A4-[5-Ethoxy-3-(1H-imidazol-1-ylcarbonyl)-2-methyl-1,4-dihydro-1,6-naphthyridin-4-yl]-3-methoxybenzonitrile

1.20 g (3.28 mmol) of the compound from Example 22A are introduced into25 ml of ethyl acetate and, after addition of 0.666 g (4.11 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature overnight. Thereaction mixture is concentrated in a rotary evaporator, and the crudeproduct obtained in this way is employed without purification forfurther reactions.

MS (Elpos): m/z=416 [M+H]⁺.

Example 24A 2-Cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate

3.00 g (18.62 mmol) of the compound from Example 10A, 3.18 g (20.48mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med.Chem. Lett. 16, 798-802 (2006)], 213 μl (3.72 mmol) of acetic acid and368 μl (3.72 mmol) of piperidine are dissolved in 50 ml of anhydrousdichloromethane and stirred under reflux with a water trap overnight.The volatile components are then removed in a rotary evaporator, and theresidue is purified by column chromatography (silica gel; mobile phase:gradient cyclohexane/ethyl acetate 7:3→1:1). 2.77 g (48% of theory) ofthe title compound are obtained as a mixture of the E/Z isomers.

LC-MS (method 7): R_(t)=2.89 and 3.00 min; MS (Elpos): m/z=299 [M+H]⁺.

Example 25A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-2,7-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

1.49 g (5.00 mmol) of the compound from Example 24A are introduced into30 ml of 2-propanol, mixed with 620 mg (5.00 mmol) of4-amino-6-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis,765-766 (1984)] and then stirred at the reflux temperature overnight.After cooling, the precipitate is filtered off, washed with diethylether and dried under high vacuum. 1.53 g (76% of theory) of the titlecompound are obtained.

LC-MS (method 3): R_(t)=1.73 min; MS (Elpos): m/z=405 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.05 (s, 3H), 2.26 (s, 3H), 2.78 (m, 2H),3.74 (s, 3H), 3.96-4.13 (m, 2H), 5.14 (s, 1H), 5.64 (d, 1H), 7.23 (dd,1H), 7.28-7.33 (m, 2H), 9.22 (s, 1H), 10.82 (s, 1H).

Example 26A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

1.52 g (3.76 mmol) of the compound from Example 25A are suspended in 40ml of triethyl orthoformate and heated to 130° C. Then, over a totalperiod of 8 hours, 10 drops of concentrated sulfuric acid are added eachhour to the reaction mixture. It is then stirred at the same temperatureovernight. After cooling, excess orthoester is removed in a rotaryevaporator, and the crude product is purified by column chromatography(silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). The productfractions are combined, the solvent is removed, and the residue is takenup in a little methanol. The crystallizing product is filtered off.Drying under high vacuum results in 1.09 g (67% of theory) of the titlecompound.

LC-MS (method 3): R_(t)=2.23 min; MS (Elpos): m/z=433 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.20 (s, 3H), 2.32 (s, 3H),2.76 (m, 2H), 3.78 (s, 3H), 3.97-4.12 (m, 4H), 5.32 (s, 1H), 6.30 (s,1H), 7.24 (d, 1H), 7.27-7.32 (m, 2H), 9.43 (s, 1H).

Example 27A4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

642 mg (2.52 mmol) of the compound from Example 26A are dissolved in 40ml of 1,2-dimethoxyethane/water (3:1 v/v), mixed with 5.04 ml (5.04mmol) of 1 N sodium hydroxide solution and stirred at room temperatureovernight. The mixture is then mixed with 30 ml of diethyl ether and 30ml of water, the organic phase is separated off, and the aqueous phaseis adjusted to pH 4-5 with 1 N hydrochloric acid. The resultingsuspension is stirred for 1 h, and the precipitated solid is thenremoved by filtration. The precipitate is washed with water and a littlediethyl ether. Drying at 40° C. in vacuo results in 642 mg (67% oftheory) of the title compound.

LC-MS (method 3): R_(t)=1.87 min; MS (Elpos): m/z=380 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.19 (s, 3H), 2.28 (s, 3H),3.74 (s, 3H), 4.05 (m, 2H), 5.28 (s, 1H), 6.27 (s, 1H), 7.20-7.28 (m,2H), 7.31 (s, 1H), 9.17 (s, 1H), 11.31 (s, 1H).

Example 28A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

2.69 g (9.00 mmol) of the compound from Example 24A are introduced into45 ml of 2-propanol, mixed with 1.17 g (9.00 mmol) of4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis,765-766 (1984)] and then stirred at the reflux temperature overnight.After cooling, the precipitate is filtered off, washed with diethylether and dried under high vacuum. 2.22 g (61% of theory) of the titlecompound are obtained.

LC-MS (method 3): R_(t)=1.75 min; MS (Elpos): m/z=405 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H),3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H),7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

Example 29A 2-Cyanoethyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

2.22 g (5.44 mmol) of the compound from Example 28A are suspended in 100ml of triethyl orthoformate and heated to 130° C. Then, over a totalperiod of 8 hours, 10 drops of concentrated sulfuric acid are added eachhour to the reaction mixture. It is then stirred at the same temperatureovernight. After cooling, excess orthoester is removed in a rotaryevaporator, and the crude product is purified by column chromatography(silica gel; mobile phase: initially dichloromethane thenisohexane/ethyl acetate 1:1). The product fractions are combined, thesolvent is removed, and the residue is crystallized from ethylacetate/diethyl ether. The precipitate is filtered off and dried underhigh vacuum. 1.80 g (77% of theory) of the title compound are obtained.

LC-MS (method 6): R_(t)=3.02 min; MS (Elpos): m/z=433 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H),2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d,1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

Example 30A4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

1.75 g (4.05 mmol) of the compound from Example 29A are dissolved in 60ml of 1,2-dimethoxyethane/water (2:1 v/v), 8.09 ml (8.09 mmol) of 1 Nsodium hydroxide solution are added, and the mixture is stirred at roomtemperature for one hour. 30 ml of diethyl ether are then added to themixture, and the aqueous phase is acidified with 6 N hydrochloric acid.The resulting precipitate is filtered off and washed with water and alittle diethyl ether. Drying in a vacuum drying oven at 40° C. resultsin 1.47 g (96% of theory) of the title compound.

LC-MS (method 7): R_(t)=2.50 min; MS (Elpos): m/z=380 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H),3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H),7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

Example 31A 2-Cyanoethyl2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

3.00 g (15.94 mmol) of the compound from Example 5A, 1.75 g (15.94 mmol)of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron55, 11985-11996 (1999)] and 2.47 g (15.94 mmol) of 2-cyanoethyl3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16,798-802 (2006)] are dissolved in 60 ml of ethanol and stirred at thereflux temperature under argon overnight. The precipitated product isthen filtered off, washed with ethanol and diethyl ether and dried underhigh vacuum. 2.30 g (35% of theory) of the title compound are obtainedin the form of beige-colored crystals.

LC-MS (method 7): R_(t)=1.59 min; MS (Elpos): m/z=418 [M+H]⁺.

Example 32A 2-Cyanoethyl5-ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate

2.20 g (5.27 mmol) of the compound from Example 31A are suspended in 80ml of triethyl orthoformate and heated to 130° C. Then, over a totalperiod of 8 hours, 5 drops of concentrated sulfuric acid are added eachhour to the reaction mixture. It is then stirred at the same temperatureovernight. After cooling, excess orthoester is removed in a rotaryevaporator, and the crude product is purified by column chromatography(silica gel; mobile phase: initially dichloromethane, then ethylacetate, finally ethyl acetate/methanol 20:1). The product fractions areconcentrated to a volume of about 5 ml. The precipitated product isfiltered off and, after washing with ethyl acetate and diethyl ether,dried under high vacuum. 282 mg (12% of theory) of the title compoundare obtained in the form of brown crystals.

LC-MS (method 3): R_(t)=1.96 min; MS (Elpos): m/z=446 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.01 (t, 3H), 2.38 (s, 6H), 2.74 (m, 2H),3.96-4.13 (m, 4H), 5.54 (s, 1H), 6.19 (s, 1H), 6.53 (d, 1H), 7.31 (t,1H), 7.67 (dd, 1H), 7.76 (d, 1H), 7.80 (dd, 1H), 9.69 (s, 1H).

Example 33A5-Ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

270 mg (0.61 mmol) of the compound from Example 32A are dissolved in 15ml of 1,2-dimethoxyethane/water (2:1 v/v), 1.21 ml (1.21 mmol) of 1 Nsodium hydroxide solution are added, and the mixture is stirred at roomtemperature for 1 h. 30 ml of diethyl ether are then added to thereaction mixture. The aqueous phase is separated off and acidified with1 N hydrochloric acid. The resulting precipitate is filtered off andwashed with water and a little diethyl ether. Drying in vacuo at 40° C.results in 167 mg (70% of theory) of the title compound.

LC-MS (method 7): R_(t)=2.01 min; MS (Elpos): m/z=393 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.02 (t, 3H), 2.33 (s, 3H), 2.35 (s, 3H),3.97 (m, 1H), 4.08 (m, 1H), 5.52 (s, 1H), 6.18 (s, 1H), 6.50 (d, 1H),7.31 (t, 1H), 7.60 (dd, 1H), 7.74 (d, 1H), 7.79 (dd, 1H), 9.42 (s, 1H),11.45 (br. s, 1H).

Example 34A 2-Cyanoethyl4-[4-bromo-2-(trifluoromethoxy)phenyl]-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

10.00 g (31.17 mmol) of the compound from Example 6A and 6.41 g (31.17mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med.Chem. Lett. 16, 798-802 (2006)] are introduced into 100 ml of 2-propanoland, after adding 4.09 g (37.17 mmol) of 4-aminopyridin-2(1H)-one[Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)],stirred at the reflux temperature for three days. After cooling, thesolvent is removed under reduced pressure, and the crude product ispurified by column chromatography (silica gel; mobile phase:dichloromethane/methanol 10:1). 7.38 g (36% of theory) of the titlecompound are obtained.

LC-MS (method 6): R_(t)=2.84 min; MS (Elpos): m/z=499 [M+H]⁺.

Example 35A 2-Cyanoethyl4-[4-bromo-2-(trifluoromethoxy)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

7.30 g (13.19 mmol) of the compound from Example 34A are suspended in150 ml of triethyl orthoformate and heated to 130° C. Then, over a totalperiod of 7 hours, 15 drops of concentrated sulfuric acid are added eachhour to the reaction mixture. It is then stirred at the same temperatureovernight. After cooling, excess orthoester is removed in a rotaryevaporator, and the crude product is purified by column chromatography(silica gel; mobile phase: cyclohexane/ethyl acetate 1:1). 4.59 g (64%of theory) of the title compound are obtained.

LC-MS (method 3): R_(t)=2.74 min; MS (Elpos): m/z=527 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.17 (t, 3H), 2.33 (s, 3H), 2.81 (m, 2H),3.99-4.21 (m, 4H), 5.29 (s, 1H), 6.50 (d, 1H), 7.31 (t, 1H), 7.37 (d,1H), 7.44 (dd, 1H), 7.78 (d, 1H), 9.63 (s, 1H).

Example 36A 2-Cyanoethyl4-[4-cyano-2-(trifluoromethoxy)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

4.59 g (8.72 mmol) of the compound from Example 35A, 758 mg (6.45 mmol)of zinc cyanide and 504 mg (0.436 mmol) oftetrakis(triphenylphosphine)palladium(0) are dissolved in 40 ml of DMFand then, divided into three mixtures, heated in a single mode microwave(Emrys Opzimizer) at 220° C. for 5 min. The individual mixtures are thenrecombined, and the solvent is removed in a rotary evaporator. The crudeproduct is taken up in ethyl acetate and filtered through kieselguhr.The organic phase is washed with water (2×) and with saturated sodiumchloride solution. After removal of the solvent by distillation, thecrude product is purified by column chromatography (silica gel; mobilephase: cyclohexane/ethyl acetate 7:3→1:1). 1.40 g (31% of theory) of thetitle compound are obtained.

LC-MS (method 3): R_(t)=2.48 min; MS (Elpos): m/z=473 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.10 (t, 3H), 2.34 (s, 3H), 2.80 (m, 2H),4.00-4.21 (m, 4H), 5.36 (s, 1H), 6.51 (d, 1H), 7.60 (d, 1H), 7.66-7.74(2H), 7.79 (d, 1H), 9.70 (s, 1H).

Example 37A4-[4-Cyano-2-(trifluoromethoxy)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

1400 mg (2.96 mmol) of the compound from Example 36A are dissolved in 35ml of 1,2-dimethoxyethane/water (2.5:1 v/v), 5.93 ml (5.93 mmol) of 1 Nsodium hydroxide solution are added, and the mixture is stirred at roomtemperature for 2 h. The reaction mixture is then mixed with 50 ml ofdiethyl ether and 50 ml of water. The aqueous phase is separated off andadjusted to a pH of 4-5 with 1 N hydrochloric acid. The resultingsuspension is then stirred for 1 h. The resulting precipitate isfiltered off and washed with water and a little diethyl ether. Drying invacuo results in 850 mg (68% of theory) of the title compound.

LC-MS (method 3): R_(t)=2.19 min; MS (Elpos): m/z=420 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.11 (t, 3H), 2.31 (s, 3H), 4.06 (m, 1H),4.13 (m, 1H), 5.37 (s, 1H), 6.49 (d, 1H), 7.51 (d, 1H), 7.65-7.72 (m,2H), 7.76 (d, 1H), 9.42 (s, 1H), 11.62 (s, 1H).

Example 38A4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

The title compound can be obtained starting from stoichiometric amountsof 4-formyl-3-methoxybenzonitrile (Example 10A),4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55,11985-11996 (1999)] and allyl 4,4,4-trifluoro-3-oxobutanoate [Moseley,J. D., Tetrahedron Lett. 46, 3179-3181 (2005)]. This entails firstly thedihydropyridine synthesis being carried out in ethanol without additionof additives at the reflux temperature overnight. The initiallyresulting intermediate allyl4-(4-cyano-2-methoxyphenyl)-2-hydroxy-5-oxo-2-(trifluoromethyl)-1,2,3,4,5,6-hexahydro-1,6-naphthyridine-3-carboxylatecan then be dehydrated with acetic acid in a literature-based process[cf. Moseley, J. D., Tetrahedron Lett. 46, 3179-3181 (2005)].Subsequently, allyl4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylatecan be obtained by reaction with triethyl orthoformate in analogy to thesynthesis of Example 29A. Final allyl ester cleavage using Wilkinson'scatalyst [tris(triphenylphosphine)rhodium(I) chloride] in acetic acidaffords the title compound [cf. Moseley, J. D., Tetrahedron Lett. 46,3179-3181 (2005)].

LC-MS (method 7): R_(t)=2.98 min; MS (Elpos): m/z=420 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.09 (t, 3H), 3.77 (s, 3H), 3.98-4.16 (m,2H), 5.37 (s, 1H), 6.73 (d, 1H), 7.19 (d, 1H), 7.34 (dd, 1H), 7.42 (d,1H), 7.78 (d, 1H), 9.62 (s, 1H).

Example 39A 2-Cyanoethyl2,8-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate

1.50 g (7.97 mmol) of the compound from Example 5A, 1.86 g (9.57 mmol)of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem.Lett. 16, 798-802 (2006)], 91 μl (1.59 mmol) of acetic acid and 158 μl(1.59 mmol) of piperidine are dissolved in 30 ml of anhydrousdichloromethane and stirred under reflux with a water trap overnight.The mixture is then washed with water, the organic phase is dried withmagnesium sulfate, and the volatile components are removed in a rotaryevaporator. 2.91 g (approx. 7.33 mmol) of the 2-cyanoethyl(2Z)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylidene]-3-oxobutanoatecrude product obtained in this way are mixed with 0.990 g (9.00 mmol) of4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis,765-766 (1984)], taken up in 40 ml of 2-propanol and stirred at thereflux temperature overnight. After cooling, the resulting precipitateis filtered off and washed with a little diethyl ether. Drying underhigh vacuum results in 1.20 g (38% of theory) of the title compound.

LC-MS (method 8): R_(t)=1.00 min; MS (Elpos): m/z=432 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=2.06 (s, 3H), 2.34 (s, 3H), 2.44 (s, 3H),2.77 (m, 2H), 3.98-4.14 (m, 2H), 5.76 (s, 1H), 6.15 (s, 1H), 6.98 (s,1H), 7.28 (t, 1H), 7.71 (dd, 1H), 7.78 (dd, 1H), 8.29 (s, 1H), 10.78(br. s, 1H).

Example 40A 2-Cyanoethyl5-ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate

1.20 g (2.78 mmol) of the compound from Example 39A and 9.25 ml (55.6mmol) of triethyl orthoformate are taken up in 30 ml of dry DMF andheated to 130° C., and 5 drops of concentrated sulfuric acid are added.After 2 h, an HPLC check shows complete conversion. After cooling, thevolatile components are removed in a rotary evaporator, and the crudeproduct is purified by MPLC (Biotage cartridge 40 M, eluent:isohexane/ethyl acetate 1:2). 640 mg (50% of theory) of the titlecompound are obtained.

LC-MS (method 9): R_(t)=0.99 min; MS (Elpos): m/z=460 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.01 (t, 3H), 2.19 (s, 3H), 2.38 (s, 3H),2.48 (s, 3H), 2.75 (m, 2H), 3.93-4.14 (m, 4H), 5.55 (s, 1H), 6.18 (s,1H), 7.30 (t, 1H), 7.63 (s, 1H), 7.67 (dd, 1H), 7.79 (dd, 1H), 8.49 (s,1H).

Example 41A5-Ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxylicacid

640 mg (1.39 mmol) of the compound from Example 40A are dissolved in 30ml of 1,2-dimethyoxyethane/water (2:1 v/v), mixed with 2.76 ml (2.76mmol) of 1 N sodium hydroxide solution and stirred at room temperaturefor 30 min. The reaction mixture is then mixed with 20 ml of diethylether. The aqueous phase is separated off, adjusted to a pH of 4-5 with1 N hydrochloric acid and extracted three times with ethyl acetate. Theorganic phases are combined and dried with magnesium sulfate. Thevolatile components are removed in a rotary evaporator. Drying in vacuoresults in 335 mg (56% of theory) of the title compound in a purity of94% (LC-MS).

LC-MS (method 8): R_(t)=1.21 min; MS (Elpos): m/z=407 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.01 (t, 3H), 2.18 (s, 3H), 2.35 (s, 3H),2.42 (s, 3H), 3.90-4.10 (m, 2H), 5.54 (s, 1H), 6.18 (s, 1H), 7.31 (t,1H), 7.58 (dd, 1H), 7.60 (s, 1H), 7.78 (dd, 1H), 8.25 (s, 1H), 11.52(br. s, 1H).

Exemplary Embodiments Example 14-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

100 mg (approx. 0.24 mmol) of the compound from Example 23A areintroduced into 3 ml of DMF. Then 2.94 mg (0.024 mmol) of4-N,N-dimethylaminopyridine and 340 μl of ammonia (28% by weightsolution in water, 2.41 mmol) are added, and the mixture is heated at100° C. for 3 h. After cooling, the crude product is directly purifiedby preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid,gradient 20:80→95:5). 32 mg (37% of theory) of the title compound areobtained.

LC-MS (method 3): R_(t)=1.57 min; MS (Elpos): m/z=365 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.07 (t, 3H), 2.13 (s, 3H), 3.83 (s, 3H),4.04 (m, 2H), 5.36 (s, 1H), 6.42 (d, 1H), 6.66 (br. s, 2H), 7.18 (d,1H), 7.29 (dd, 1H), 7.38 (d, 1H), 7.67 (d, 1H), 8.80 (s, 1H).

Example 24-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

640 mg (1.69 mmol) of the compound from Example 27A are introduced into30 ml of ethyl acetate and, after addition of 342 mg (2.11 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLCcheck (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1 ordichloromethane/methanol 9:1) shows complete conversion. The volatilecomponents are removed in a rotary evaporator, and the residue is takenup in 20 ml of DMF. Then 2.36 ml of ammonia (28% by weight solution inwater, 16.87 mmol) are added, and the reaction mixture is heated at 50°C. for 8 h. The solvent is distilled out under reduced pressure, and theresidue is purified by preparative HPLC (eluent: acetonitrile/water with0.1% formic acid, gradient 20:80→95:5). 368 mg (58% of theory) of thetitle compound are obtained.

LC-MS (method 7): R_(t)=1.91 min; MS (Elpos): m/z=379 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.05 (t, 3H), 2.13 (s, 3H), 2.19 (s, 3H),3.84 (s, 3H), 4.02 (q, 2H), 5.32 (s, 1H), 6.25 (s, 1H), 6.62 (br. s,2H), 7.16 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 8.71 (s, 1H).

Example 3ent-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,7-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide[(−)-enantiomerand (+)-enantiomer]

The racemate from Example 2 can be fractionated into its enantiomers onthe preparative scale by chiral phase HPLC [column: Chiralpak IA, 250mm×20 mm; eluent: methyl tert-butyl ether/methanol 85:15 (v/v); flowrate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm].

(−)-Enantiomer:

HPLC: R_(t)=5.28 min, ee>98% [column: Chiralpak IA, 250 mm×4.6 mm;eluent: methyl tert-butyl ether/methanol 80:20 (v/v); flow rate: 1ml/min; temperature: 25° C.; UV detection: 220 nm];

specific rotation (chloroform, 589 nm, 19.8° C., c=0.50500 g/100 ml):−239.3°.

A single crystal X-ray structural analysis revealed an S configurationat the C* atom for this enantiomer.

(+)-Enantiomer:

HPLC: R_(t)=4.50 min, ee>99% [column: Chiralpak IA, 250 mm×4.6 mm;eluent: methyl tert-butyl ether/methanol 80:20 (v/v); flow rate: 1ml/min; temperature: 25° C.; UV detection: 220 nm];

specific rotation (chloroform, 589 nm, 20° C., c=0.51000 g/100 ml):+222.7°.

Example 44-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

1.46 g (3.84 mmol) of the compound from Example 30A are introduced into50 ml of ethyl acetate and, after addition of 777 mg (4.79 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLCcheck (silica gel; mobile phase: ethyl acetate) shows completeconversion. The volatile components are removed in a rotary evaporator,and the residue is taken up in 20 ml of DMF. Then 10.74 ml of ammonia(28% by weight solution in water, 76.8 mmol) are added, and the reactionmixture is heated at 100° C. for 30 min. The solvent is distilled outunder reduced pressure, and the residue is purified by preparative HPLC(eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5).The residue after concentration of the product fractions is dissolved in40 ml of dichloromethane/methanol (1:1 v/v) and mixed with 100 ml ofethyl acetate. The solvent is concentrated to a volume of about 20 ml,whereupon the product crystallizes. The precipitate is filtered off andwashed with a little diethyl ether. Drying at 40° C. in a vacuum dryingoven results in 1.40 g (96% of theory) of the title compound.

LC-MS (method 3): R_(t)=1.64 min; MS (Elpos): m/z=379 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H),3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14(d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 5ent-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide[(−)-enantiomerand (+)-enantiomer]

The racemate from Example 4 can be fractionated into its enantiomers onthe preparative scale by chiral phase HPLC [column: 680 mm×40 mm; silicagel phase based on the chiral selectorpoly(N-methacryloyl-D-leucine-dicyclopropylmethylamide; eluent: ethylacetate; temperature: 24° C.; flow rate: 80 ml/min; UV detection: 260nm].

(−)-Enantiomer:

HPLC: R_(t)=2.48 min, ee=99.6% [column: 250 mm×4.6 mm; silica gel phasebased on the chiral selectorpoly(N-methacryloyl-D-leucine-dicyclopropylmethylamide; eluent: ethylacetate; temperature: 24° C.; flow rate: 2 ml/min; UV detection: 260nm];

specific rotation (chloroform, 589 nm, 19.7° C., c=0.38600 g/100 ml):−148.8°.

A single crystal X-ray structural analysis revealed an S configurationat the C* atom for this enantiomer.

(+)-Enantiomer:

HPLC: R_(t)=4.04 min, ee=99.3% [column: 250 mm×4.6 mm; silica gel phasebased on the chiral selectorpoly(N-methacryloyl-D-leucine-dicyclopropylmethylamide; eluent: ethylacetate; temperature: 24° C.; flow rate: 2 ml/min; UV detection: 260nm];

specific rotation (chloroform, 589 nm, 19.8° C., c=0.36300 g/100 ml):+153.0°.

Example 65-Ethoxy-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

155 mg (0.395 mmol) of the compound from Example 31A are introduced into10 ml of THF and, after addition of 80.1 mg (0.494 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLCcheck (silica gel; mobile phase: ethyl acetate ordichloromethane/methanol 9:1) shows complete conversion. The volatilecomponents are removed in a rotary evaporator, and the residue is takenup in 3 ml of DMF. Then 553 mg of ammonia (28% by weight solution inwater, 3.95 mmol) are added, and the reaction mixture is heated at 100°C. for 10 min. The solvent is removed under reduced pressure, and theresidue is purified by preparative HPLC (eluent: acetonitrile/water with0.1% formic acid, gradient 20:80→95:5). 30 mg (19% of theory) of thetitle compound are obtained.

LC-MS (method 6): R_(t)=1.17 min; MS (Elpos): m/z=392 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=0.96 (t, 3H), 2.09 (s, 3H), 2.36 (s, 3H),3.94 (m, 1H), 4.03 (m, 1H), 5.59 (s, 1H), 6.19 (s, 1H), 6.42 (d, 1H),6.66 (br. s, 1H), 7.00 (br. s, 1H), 7.31 (t, 1H), 7.53 (dd, 1H), 7.68(d, 1H), 7.79 (dd, 1H), 8.83 (s, 1H).

Example 74-[4-Cyano-2-(trifluoromethoxy)phenyl]-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

200 mg (0.477 mmol) of the compound from Example 37A are introduced into5 ml of ethyl acetate and, after addition of 96.7 mg (0.596 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature overnight (TLCcheck: insufficient reaction). Then 1 ml of DMF is added, and themixture is stirred at room temperature for a further night (TLC check:complete conversion). The volatile components are removed in a rotaryevaporator, and the residue is taken up in 4 ml of DMF. Then 663 μl ofammonia (28% by weight solution in water, 4.77 mmol) are added, and thereaction mixture is heated at 100° C. in a closed vessel overnight.After cooling, the solvent is removed under reduced pressure, and theresidue is purified by preparative HPLC (eluent: acetonitrile/water with0.1% formic acid, gradient 20:80→95:5). 140 mg (70% of theory) of thetitle compound are obtained.

LC-MS (method 6): R_(t)=2.26 min; MS (Elpos): m/z=419 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.04 (t, 3H), 2.04 (s, 3H), 4.06 (m, 2H),5.42 (s, 1H), 6.41 (d, 1H), 6.80 (br. s, 1H), 6.97 (br. s, 1H), 7.45 (d,1H), 7.68-7.74 (m, 3H), 8.82 (d, 1H).

Example 84-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2-(trifluoromethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

180 mg (0.429 mmol) of the compound from Example 38A are introduced into5 ml of ethyl acetate and, after addition of 87.0 mg (0.537 mmol) of1,1′-carbonyldiimidazole, stirred at room temperature for two hours.Complete conversion is established by a TLC check. The volatilecomponents are removed in a rotary evaporator, and the residue is takenup in 4 ml of DMF. Then 597 μl of ammonia (28% by weight solution inwater, 4.29 mmol) are added, and the reaction mixture is heated at 100°C. in a closed vessel for three hours. After cooling, the solvent isremoved under reduced pressure, and the residue is purified bypreparative HPLC (eluent: acetonitrile/water with 0.1% formic acid,gradient 20:80→95:5). 10 mg (5% of theory) of the title compound areobtained.

LC-MS (method 3): R_(t)=1.85 min; MS (Elpos): m/z=419 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.03 (t, 3H), 3.79 (s, 3H), 3.96-4.11 (m,2H), 5.37 (s, 1H), 6.62 (d, 1H), 7.08-7.14 (m, 2H), 7.32 (dd, 1H),7.37-7.46 (m, 2H), 7.73 (d, 1H), 9.18 (s, 1H).

Example 95-Ethoxy-2,8-dimethyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

335.0 mg (0.824 mmol) of the compound from Example 41A are introducedinto 10 ml of ethyl acetate, and 167.1 mg (0.537 mmol) of1,1′-carbonyldiimidazole are added. The suspension is then stirred atroom temperature overnight. Since a clear solution is not produced, 2 mlof DMF are added and the mixture is stirred at room temperature for afurther two hours. Complete conversion is then established by TLC check.The volatile components are removed in a rotary evaporator, and theresidue is taken up in 4 ml of DMF. Then 2.293 ml of ammonia (28% byweight solution in water, 16.5 mmol) and 10.1 mg of4-N,N-dimethylaminopyridine are added. The reaction mixture is heated at100° C. in a closed vessel for thirty minutes. After cooling, thesolvent is removed under reduced pressure, and the residue is purifiedby preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid,gradient 20:80→95:5). The product fractions are concentrated and theresidue is taken up in a little dichloromethane, and diisopropyl etheris added until the solution is cloudy. The precipitated solid isisolated and dried in vacuo. 207 mg (59% of theory) of the titlecompound are obtained.

LC-MS (method 9): R_(t)=0.67 min; MS (Elpos): m/z=406 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=0.94 (t, 3H), 2.13 (s, 3H), 2.14 (s, 3H),2.34 (s, 3H), 3.90 (m, 1H), 4.00 (m, 1H), 5.58 (s, 1H), 6.18 (s, 1H),6.70 (br. s, 1H), 7.06 (br. s, 1H), 7.30 (t, 1H), 7.50 (dd, 1H), 7.56(s, 1H), 7.71 (s, 1H), 7.78 (dd, 1H).

B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY

Abbreviations: DMEM Dulbecco's modified Eagle medium DNAdeoxyribonucleic acid FCS fetal calf serum HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid PCR polymerase chainreaction Tris tris-(hydroxymethyl)methylamine

The advantageous pharmacological properties of the compounds of theinvention can be shown in the following assays:

1. Cellular In Vitro Assay to Determine the Inhibitory MR Activity andMR Selectivity Compared with Other Steroid Hormone Receptors

Antagonists of the human mineralocorticoid receptor (MR) are identified,and the activity of the compounds described herein is quantified withthe aid of a recombinant cell line. The cell is originally derived froma hamster ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC:American Type Culture Collection, VA 20108, USA).

An established chimera system in which the ligand-binding domains ofhuman steroid hormone receptors are fused to the DNA-binding domain ofthe yeast transcription factor GAL4 is used in this CHO K1 cell line.The GAL4-steroid hormone receptor chimeras produced in this way arecotransfected and stably expressed with a reporter construct in the CHOcells.

Clonings:

To generate the GAL4-steroid hormone receptor chimeras, the GAL4 DNAbinding domain (amino acids 1-147) from the vector pFC2-dbd (fromStratagene) is cloned with the PCR-amplified ligand-binding domains ofthe mineralocorticoid receptor (MR, amino acids 734-985), of theglucocorticoid receptor (GR, amino acids 443-777), of the progesteronereceptor (PR, amino acids 680-933) and of the androgen receptor (AR,amino acids 667-919) into the vector pIRES2 (from Clontech). Thereporter construct, which comprises five copies of the GAL4 binding siteupstream of a thymidine kinase promoter, leads to expression offirefly-luciferase (Photinus pyralis) after activation and binding ofthe GAL4-steroid hormone receptor chimeras by the respective specificagonists aldosterone (MR), dexamethasone (GR), progesterone (PR) anddihydrotestosterone (AR).

Assay Procedure:

The MR, GR, PR and AR cells are plated out in medium (Optimem, 2.5% FCS,2 mM glutamine, 10 mM HEPES) in 96- (or 384- or 1536-) well microtiterplates on the day before the assay and are kept in a cell incubator (96%humidity, 5% v/v CO₂, 37° C.). On the day of the assay, the substancesto be tested are taken up in the abovementioned medium and added to thecells. About 10 to 30 minutes after addition of the test substances, therespective specific agonists of the steroid hormone receptors are added.After a further incubation time of 5 to 6 hours, the luciferase activityis measured with the aid of a video camera. The measured relative lightunits as a function of the substance concentration result in a sigmoidalstimulation curve. The IC₅₀ values are calculated with the aid of theGraphPad PRISM computer program (Version 3.02).

Table A shows the IC₅₀ values (MR) of representative exemplarycompounds:

TABLE A Example No. MR IC₅₀ [nM] 1 35 4 23 5 16 [(−)-enantiomer]2. In Vitro Assay to Determine Possible Binding Activity to the L-TypeCalcium Channel

Membrane preparations of the cerebral cortex of Wistar rats serve asstarting material for a radioactive binding assay which is described indetail in the literature as standard assay [Ehlert, F. J., Roeske, W.R., Itoga E., Yamamura, H. I., Life Sci. 30, 2191-2202 (1982); Gould, R.J., Murphy, K. M. M., Snyder, S. H., Proc. Natl. Acad. Sci. U.S.A. 79,3656-3660] and is used in contract investigations by commercial servicesuppliers (e.g. MDS Pharma Services). In this binding assay, serialdilutions of the test compounds in DMSO are incubated with the membranepreparations and the tritium-labeled ligand nitrendipine (0.1 nM) in a50 mM TrisHCl buffer, pH 7.7, at 25° C. typically for 90 minutes, andthe specific binding of the test compounds is determined by quantifyingthe specifically displaced, radiolabelled ligand. IC₅₀ values aredetermined by a nonlinear regression analysis.

The IC₅₀ value determined in this L-type calcium channel binding assayfor a conventional calcium antagonist of the dihydropyridine type suchas, for example, nitrendipine is 0.3 nM, whereas the IC₅₀ values forinvestigated examples of the compounds of the invention described hereinare >1 μM and thus the affinity shown for the L-type calcium channel isreduced by a factor of at least 3000. Compounds with such a low residualbinding affinity for the L-type calcium channel no longer showpronounced hemodynamic effects mediated by the L-type calcium channel invivo.

3. In Vivo Assay for Detecting the Cardiovascular Effect: DiuresisInvestigations on Conscious Rats in Metabolism Cages

Wistar rats (bodyweight 250-350 g) are kept with free access to feed(Altromin) and drinking water. From about 72 hours before the start ofthe test, the animals receive instead of the normal feed exclusivelysalt-reduced feed with a sodium chloride content of 0.02% (ssniff R/M−H,10 mm with 0.02% Na, 50602-E081, ssniff Spezialdiaten GmbH, D-59494Soest). During the test, the animals are housed singly in metabolismcages suitable for rats of this weight class (from Tecniplast GermanyGmbH, D-82383 Hohenpeiβenberg) with free access to salt-reduced feed anddrinking water for about 24 hours. At the start of the test, thesubstance to be tested is administered into the stomach by means ofgavage in a volume of 0.5 ml/kg of bodyweight of a suitable solvent.Control animals receive only solvent. Controls and substance tests arecarried out in parallel on the same day. Control groups andsubstance-dose groups each consist of 3 to 6 animals. During the test,the urine excreted by the animals is continuously collected in areceiver on the base of the cage. The urine volume per unit time isdetermined separately for each animal, and the concentration of thesodium and potassium ions excreted in the urine is measured by standardmethods of flame photometry. The sodium/potassium ratio is calculatedfrom the measurements as a measure of the effect of the substance. Themeasurement intervals are typically the period up to 8 hours after thestart of the test (day interval) and the period from 8 to 24 hours afterthe start of the test (night interval). In a modified test design, theurine is collected and measured at intervals of two hours during the dayinterval. In order to obtain a sufficient amount of urine for thispurpose, the animals receive a defined amount of water by gavage at thestart of the test and then at intervals of two hours.

4. DOCA/Salt Model

Administration of deoxycorticosterone acetate (DOCA) in combination witha high-salt diet and unilateral kidney removal in rats induceshypertension which is characterized by relatively low renin levels. As aconsequence of this endocrine hypertension (DOCA is a direct precursorof aldosterone), there is, depending on the chosen DOCA concentration,cardiac hypertrophy and further end organ damage, e.g. of the kidney,which is characterized inter alia by protein urea andglomerulosclerosis. It is thus possible to investigate test substancesin this rat model for the presence of an antihypertrophic and endorgan-protecting effect.

Approximately 8-week old (body weight between 250 and 300 grams) maleSprague-Dawley (SD) rats undergo left uninephrectomy. For this purpose,the rats are anesthetized with 1.5-2% isoflurane in a mixture of 66% N₂Oand 33% O₂, and the kidney is removed through a flank incision.So-called sham-operated animals from which no kidney is removed serve aslater control animals.

Uninephrectomized SD rats receive 1% sodium chloride in the drinkingwater and a subcutaneous injection of deoxycorticosterone acetate(dissolved in sesame oil; from Sigma) injected between the shoulderblades once a week (high dose: 100 mg/kg/week s.c.; normal dose: 30mg/kg/week s.c.).

The substances which are to be investigated for their protective effectin vivo are administered by gavage or via the feed (from Ssniff). Oneday before the start of the test, the animals are randomized andassigned to groups with an identical number of animals, usually n=10,Throughout the test, drinking water and feed are available ad libitum tothe animals. The substances are administered via the feed or once a dayby gavage for 4-8 weeks Animals serving as placebo group are treated inthe same way but receive either only the solvent or the feed withouttest substance.

The effect of the test substances is determined by measuring hemodynamicparameters [blood pressure, heart rate, inotropism (dp/dt), relaxationtime (tau), maximum left ventricular pressure, left-ventricularend-diastolic pressure (LVEDP)], determining the weight of the heart,kidney and lung, measuring the protein excretion, and by measuring geneexpression of biomarkers (e.g. ANP, atrial natriuretic peptide, and BNP,brain natriuretic peptide) by means of RT/TaqMan PCR after RNA isolationfrom cardiac tissue.

Statistical analysis takes place using Student's t test after previousexamination of the variances for homogeneity.

5. In Vivo Assay for Detecting Anti-Mineralocorticoid Activity onAnesthetized Dogs

Male or female mongrel dogs (mongrels, Marshall BioResources, USA) witha weight between 20 and 30 kilograms are anesthetized with pentobarbital(30 mg/kg intravenously; Narcoren®, Merial, Germany). Alcuroniumchloride (3 mg/animal intravenously; Alloferin®, ICN Pharmaceuticals,Germany) is used in addition as muscle relaxant. The dogs are intubatedand ventilated with an oxygen/ambient air mixture (40/60 Vol.-%) (about5-6 liters/min). The ventilation takes place with a ventilator suppliedby Draeger (Sulla 808) and is monitored with a CO₂ analyzer (fromEngstrom). The anesthesia is maintained by continuous infusion ofpentobarbital (50 μg/kg/min) or isoflurane (1-2 Vol.-%). Fentanyl (10μg/kg/h) is used as analgesic.

The primary aim of the test is to investigate the effect of testcompounds with antimineralocorticoid receptor activity on thealdosterone-induced sodium retention. The procedure for this isanalogous to a published method [H. P. Ramjoe, U. M. Bucher, J. Richterund M. De Gasparo, Anti-mineralocorticoid activity of three novelaldosterone antagonists in the conscious dog and in man, in: DiureticsII: Chemistry, Pharmacology, and Clinical Applications, J. B. Puschettund A. Greenberg (Ed.), Elsevier Science Publishing Co., Inc., 1987]. Acontinuous infusion of aldosterone (0.6 μg/kg/h) leads after 3 hours toa decrease in the sodium/potassium ratio in the urine (sodium andpotassium are determined by flame photometry). The test substance isadministered intravenously, intraduodenally or orally, continuing thealdosterone infusion. Spironolactone is used as positive control andincreases the sodium/potassium ratio in the urine dose-dependently.

To ensure constant hemodynamics and to measure functional cardiovascularparameters, the dog undergoes hemodynamic monitoring and instrumentationin the following way:

-   -   introduction of a bladder catheter to measure the urine flow and        the urine composition;    -   attachment of ECG leads to the extremities for ECG measurement;    -   introduction into the femoral artery of a Fluidmedic PE 300 tube        which is filled with saline and which is connected to a pressure        sensor (from Braun, Melsungen, Germany) for measuring the        systemic blood pressure;    -   introduction of a Millar Tip catheter (type 350 PC, Millar        Instruments, Houston, USA) through the left atrium or through a        port secured in the carotid artery for measuring cardiac        hemodynamics;    -   introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards,        Irvine, USA) via the jugular vein into the pulmonary artery to        measure the cardiac output, oxygen saturation, pulmonary        arterial pressures and central venous pressure;    -   attachment of an ultrasonic flow measuring probe (Transsonic        Systems, Ithaca, USA) to the descending aorta to measure the        aortic flow;    -   attachment of an ultrasonic flow measuring probe (Transsonic        Systems, Ithaca, USA) to the left coronary artery to measure the        coronary flow;    -   siting a Braunüle in the cephalic vein for infusing        pentobarbital, liquid replacement and for blood sampling        (determination of the plasma levels of substance or other        clinical blood parameters);    -   siting of a Brauüle in the saphenous vein, for fentanyl and        aldosterone infusion and for administration of substance.

The primary signals are amplified if necessary (Gould amplifier, GouldInstrument Systems, Valley View, USA or Edwards Vigilance-Monitor,Edwards, Irvine, USA) and subsequently fed into the Ponemah system(DataSciences Inc., Minneapolis, USA) for analysis. The signals arerecorded continuously throughout the test period, further processeddigitally by this software and averaged over 30 seconds.

6. Chronic Myocardial Infarction Model in Concious Rats

Male Wistar rats (280-300 g body weight; Harlan-Winkelmann) areanesthetized with 5% isoflurane in an anesthesia cage, connected to aventilation pump (ugo basile 7025 rodent, 50 strokes/min, 7 ml) andventilated with 2% isoflurane/N₂O/O₂. The body temperature is maintainedat 37-38° C. by a heating mat. 0.05 mg/kg Temgesic is givensubcutaneously as analgesic. The chest is opened laterally between thethird and fourth rib, and the heart is exposed. The coronary artery ofthe left ventricle (LAD) is permanently ligated with an occlusion thread(prolene 1 metric 5-0 ethicon1H) passed underneath shortly below itsorigin (below the left atrium). The occurrence of a myocardialinfarction is monitored by an ECG measurement (Cardioline, Remco,Italy). The thorax is reclosed and the muscle layers are sutured withEthibond excel 1 metric 5/0 6951H and the epidermis is sutured withEthibond excel 3/0 6558H. The surgical suture is wetted with a spraydressing (e.g. Nebacetin®N in spray dressing, active ingredient:neomycin sulfate) and then the anesthesia is terminated.

One week after the LAD occlusion, the size of the myocardial infarct isestimated by echocardiography (Sequoia 512, Acuson). The animals arerandomized and divided into individual treatment groups and a controlgroup without substance treatment. A sham group in which only thesurgical procedure, but not the LAD occlusion, was performed is includedas further control.

Substance treatment takes place over 8 weeks by gavage or by adding thetest compound to the feed or drinking water. The animals are weighedeach week, and the water and feed consumption is determined every 14days.

After treatment for 8 weeks, the animals are again anesthetized (2%isoflurane/N₂O/air) and a pressure catheter (Millar SPR-320 2F) isinserted via the carotid artery into the left ventricle. The heart rate,left ventricular pressure (LVP), left-ventricular end-diastolic pressure(LVEDP), contractility (dp/dt) and relaxation rate (τ) are measuredthere and analyzed with the aid of the Powerlab systems (AD Instruments,ADI-PWLB-4SP) and the Chart 5 software (SN 425-0586). A blood sample isthen taken to determine the blood levels of the substance and plasmabiomarkers, and the animals are sacrificed. The heart (heart chambers,left ventricle with septum, right ventricle), liver, lung and kidney areremoved and weighed.

7. Stroke-Prone Spontaneously Hypertensive Rat Model

Administration of sodium chloride to the so-called stroke-pronespontaneously hypertensive rat (SP-SHR) leads in this modelparadoxically to abolition of the physiological salt-induced repressionof renin and angiotensin release after a few days. Thus, thehypertension in the SP-SHR animals is characterized by a relatively highrenin level. As a consequence of the developing hypertension there ispronounced end-organ damage to the heart and the kidney, which ischaracterized inter alia by proteinurea and glomerulosclerosis, andgeneral vascular changes. Thus, in particular strokes may developprimarily through cerebrovascular lesions (“stroke-prone”) which lead toa high mortality of the untreated animals. It is thus possible toinvestigate test substances for blood pressure-lowering and endorgan-protecting effect in this rat model.

Approximately 10-week old male SP-SH rats (body weight between 190 and220 g) are randomized and assigned to groups with an equal number ofanimals, usually n=12-14, one day before the start of the test.Throughout the test, drinking water containing sodium chloride (2% NaCl)and feed are available ad libitum to the animals. The substances areadministered once a day by gavage or with the feed (Ssniff, Germany) for6-8 weeks Animals treated in the same way but receiving either only thesolvent or the feed without test substance serve as placebo group. Inthe context of a mortality study, the test is terminated when about 50%of the placebo-treated animals have died.

The effect of the test substances is followed by measuring the changesin the systolic blood pressure (via a tail cuff) and the proteinexcretion in the urine. There are post mortem determinations of theweights of heart, kidney and lung, and histopathological analyses of theheart, kidney and brain with semiquantitative scoring of thehistological changes. Various biomarkers (e.g. ANP, atrial natriureticpeptide, and BNP, brain natriuretic peptide, KIM-1, kidney-inducedmolecule 1, osteopontin-1) are determined by RT/TaqMan PCR following RNAisolation from cardiac and renal tissue or serum or plasma.

Statistical analysis is carried out with Student's t test after previousexamination of the variances of homogeneity.

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted into pharmaceuticalpreparations in the following ways:

Tablet:

Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are mixed with the magnesium stearate for 5 minutes afterdrying. This mixture is compressed with a conventional tablet press (seeabove for format of the tablet). A guideline compressive force for thecompression is 15 kN.

Suspension which can be administered orally:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound of the inventionis added to the suspension. The water is added while stirring. Themixture is stirred for about 6 h until the swelling of the Rhodigel iscomplete.

Solution which can be administered orally:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400. 20 g of oral solution correspond to a singledose of 100 mg of the compound according to the invention.

Production:

The compound of the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

i.v. Solution:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically tolerated solvent (e.g.isotonic saline solution, 5% glucose solution and/or 30% PEG 400solution). The solution is sterilized by filtration and used to fillsterile and pyrogen-free injection containers.

The invention claimed is:
 1. A compound of the formula (I)

in which D is N or C—R⁴, in which R⁴ is hydrogen, fluorine,trifluoromethyl or (C₁-C₄)-alkyl, Ar is a group of the formula

in which * is the linkage point, R⁵ is hydrogen, fluorine, chlorine,cyano, nitro, trifluoromethyl or (C₁-C₄)-alkyl, R⁶ is hydrogen orfluorine, R⁷ is halogen, (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxyor trifluoromethoxy, R⁸ is cyano or nitro, R⁹ is hydrogen, halogen,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, (C₁-C₄)-alkylthio ordi-(C₁-C₄)-alkylamino, it being possible for the alkyl group in said(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy and (C₁-C₄)-alkylthio radicals in eachcase to be substituted up to three times by fluorine, or phenyl, whichmay be substituted by halogen, (C₁-C₄)-alkyl or trifluoromethyl, R¹⁰ ishydrogen, halogen or (C₁-C₄)-alkyl, E is CH, C—R⁷ or N, and n is thenumber 0, 1 or 2, it being possible in the case where the substituent R⁷occurs more than once for its meanings to be identical or different, R¹is (C₁-C₄)-alkyl which may be substituted up to three times by fluorine,R² is (C₁-C₆)-alkyl which may be substituted by (C₃-C₇)-cycloalkyl or upto three times by fluorine, or is a group of the formula —SO₂—R¹¹ inwhich R¹¹ is (C₁-C₆)-alkyl, trifluoromethyl, (C₃-C₇)-cycloalkyl, phenylor 5- or 6-membered heteroaryl having up to two heteroatoms from theseries N, O and/or S, it being possible for phenyl and heteroaryl inturn each to be substituted once or twice, identically or differently,by halogen, cyano, nitro, (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxyand/or trifluoromethoxy, and R³ is hydrogen, fluorine, trifluoromethylor (C₁-C₄)-alkyl, or a salt thereof.
 2. A compound of the formula (I) asclaimed in claim 1, in which D is C—R⁴ in which R⁴ is hydrogen, methylor trifluoromethyl, Ar is a group of the formula

in which * is the linkage point, R⁵ is hydrogen, fluorine, chlorine orcyano, R⁸ is cyano or nitro, and R⁹ is chlorine, bromine, (C₁-C₄)-alkyl,trifluoromethyl, (C₁-C₄)-alkoxy, trifluoromethoxy, (C₁-C₄)-alkylthio ortrifluoromethylthio, R¹ is methyl or trifluoromethyl, R² is(C₁-C₄)-alkyl, trifluoromethyl or a group of the formula —SO₂—R¹¹ inwhich R¹¹ is (C₁-C₄)-alkyl or trifluoromethyl, and R³ is hydrogen,methyl or trifluoromethyl, or a salt thereof.
 3. A compound of theformula (I) as claimed in claim 1, in which D is C—R⁴ in which R⁴ ishydrogen or methyl, Ar is a group of the formula

in which * is the linkage point and R⁹ is ethyl, methoxy ortrifluoromethoxy, R¹ is methyl or trifluoromethyl, R² is methyl, ethyl,n-propyl or isopropyl and R³ is hydrogen or methyl, or a salt thereof.4. A compound as claimed in claim 1, having one of the followingstructures:

or a salt thereof.
 5. A compound as claimed in claim 1, having one ofthe following structures:

or a salt thereof.
 6. A process for preparing compounds of the formula(I) as defined in claim 1, comprising reacting a compound of the formula(II)

in which Ar has the meaning indicated in claim 1, in an inert solvent,optionally, in the presence of an acid, an acid/base combination and/ora dehydrating agent, with a compound of the formula (III)

in which R¹ has the meaning indicated in claim 1, and T is allyl or2-cyanoethyl, to give a compound of the formula (IV)

in which Ar, T and R¹ each have the meanings indicated above, condensingthe compound of formula (IV) in an inert solvent with a compound of theformula (V)

in which D and R³ have the meanings indicated in claim 1, to give acompound of the formula (VI)

in which Ar, D, T, R¹ and R³ each have the meanings indicated above,alkylating a compounds of the formula (VI) in an inert solvent,optionally, in the presence of a base, with a compound of the formula(VII) or a trialkyloxonium salt of the formula (VIII)

in which R¹² is (C₁-C₆)-alkyl which may be substituted by(C₃-C₇)-cycloalkyl or up to three times by fluorine, R¹²A is methyl orethyl, X is a leaving group such as, for example, halogen, mesylate,tosylate or triflate, and Y⁻ is a non-nucleophilic anion such as, forexample, tetrafluoroborate, or in the presence of an acid with atrialkyl orthoformate of the formula (IX)

in which R^(12A) has the meaning indicated above, to give a compounds ofthe formula (X-A)

in which Ar, D, T, R¹, R³ and R¹² each have the meanings indicatedabove, or reacting the compounds of the formula (VI) in an inert solventin the presence of a base with a compound of the formula (XI)

in which R¹¹ has the meaning indicated in claim 1, to give a compound ofthe formula (X-B)

in which Ar, D, T, R¹, R³ and R¹¹ each have the meanings indicatedabove, eliminating the ester group T in the compounds of the formula(X-A) or (X-B) to give a carboxylic acids of the formula (XII)

in which Ar, D, R¹, R² and R³ each have the meanings indicated in claim1, then converting the compound of formula (CII) with1,1′-carbonyldiimidazole into the imidazolides of the formula (XIII)

in which Ar, D, R¹, R² and R³ each have the meanings indicated above,and reacting the compound of formula (XIII) in an inert solvent,optionally in the presence of an auxiliary base, with ammonia to give anamide of the formula (I), optionally, separating compounds of theformula (I) produced as described above by method known to the skilledworker into their enantiomers and/or diastereomers, and, optionally,converting the compound of formula (I) with an appropriate (i) solventand/or (ii) base or acid into a salt thereof.
 7. A pharmaceuticalcomposition comprising a compound of the formula (I) as defined in claim1 in combination with an inert, non-toxic, pharmaceutically suitableexcipient.
 8. The pharmaceutical composition of claim 7 furthercomprising one or more further active ingredients selected from thegroup consisting of ACE inhibitors, renin inhibitors, angiotensin IIreceptor antagonists, beta-blockers, acetylsalicylic acid, diuretics,calcium antagonists, statins, digitalis (digoxin) derivatives, calciumsensitizers, nitrates and antithrombotics.
 9. The pharmaceuticalcomposition as claimed in claim 7 for the treatment of aldosteronism,high blood pressure, chronic heart failure, the sequelae of a myocardialinfarction, cirrhosis of the liver, renal failure and stroke.
 10. Acompound having the following structure:

or a salt thereof.